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Being a roguelike with many items that changes your playstyle, there are a whole lot of ways to break this game.
Note that any game breaker may be balanced simply being hard to find/get. Due to the random nature of the game, there may not be a single one listed during a run, but also due to the difficulty the game has, it may be required to have at least one of the game breakers to simply get through. Put simply: despite the number of game breakers, you may not find one, or they may be balanced during the later levels of the game.

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So good luck. You'll need them in order to take down hard bosses such as Mother, Delirium or The Beast. Especially with The Lost. Or it's Tainted counterpart.


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    Original Game and Wrath Of The Lamb 
  • Meatboy at level 3 and beyond. He chases down enemies with a cheery smile and blocks bullets. It takes a while to get him, but he'll wipe out most enemies without your input. On the other hand, he can also sometimes push bombs away from where you place them.
    • He's even more broken during the "Meat 4 Evar" challenge, which starts you with 1 fully assembled Meatboy and allows you to build another one.
  • The Battery, which regenerates three points on a spacebar item if you wait in a room with enemies long enough. This means a charged item every two rooms, even on the longest charging items. If you can blow the doors open or exit through a secret door (x-ray glasses, for example), it's effectively an infinite charge. Combine this with the 9-volt (plus two charge points automatically) and it works for every single room. Now combine it with My Little Unicorn for invincibility, Prayer Card for limitless health, or a myriad of other items for all sorts of awesome abilities.
    • Additionally, if you use a fully charged item, the 3 charges per room limit resets. This means entering a room with 3 charges, waiting to use the item and waiting again with an enemy still present will yield a total of six bars per room, no 9-volt required. Find a room with an easy enemy (like a single doppelganger in the womb or utero) and your supply of bombs can be entirely converted to a supply of blue hearts by combining the battery with a nail or book of revelations. With Ipecac, fetus in a jar, or epic fetus, you can create as many blue hearts as you have the patience to generate!
  • And then there's the Habit upgrade, which refills three bars worth of charges every time you take damage (usually in half-heart increments), plus the Yum Heart, which refills a full heart per six charges, makes you functionally invincible until you get to the later floors where you take damage in full-heart increments, and even then functionally doubles your life total. Better yet, it gives you unlimited chances at the Blood Bank, giving you oodles of coins and a very good chance to pick up a Blood Bag, which extends your heart meter. All this also gives you a lot more latitude to purchase powerful Devil Room items (which permanently reduce your heart meter).
  • Flight plus the Ouija board (which lets you shoot through rocks), or the Spirit of the Night item which combines them. Projectiles and most enemies will not be able to touch you if you're floating over an obstacle, and their projectiles can't penetrate the rocks, but yours will still hit them. You could theoretically beat some bosses (like Chad) and many other rooms by hovering over a rock and holding down the fire button.
  • Mom's Bra or the Book of Shadows can basically win a room by themselves or put the serious hurt on a boss during their duration and can be used once every three rooms. The Book of Shadows gets a special mention because if you have Poison Touch from The Virus to go with it, you've essentially got My Little Unicorn with a faster recharge rate. Mom's Bra (or Mom's Contacts, though not as reliably) does protect you from collision damage, only with it the bosses won't be running away while you drain two thirds of their lifebar with The Virus.
  • If you've mastered fighting Wrath's ability to kick bombs, Dr. Fetus becomes this, giving you the ability to shoot infinite bombs.
    • Master nothing. Add Bobby-Bomb (homing bombs), and who needs aiming? Additional items like Ouija Board (bombs pass through walls), flight (so you can too), and Mr. Mega (HUGE bomb) makes the entire game a cakewalk. Even Isaac goes down like nothing. The best part about these extras? Collecting Dr. Fetus actually rigs the item rooms, making it more likely that Bobby-Bomb and Mr. Mega will appear.
    • If you know how to use it, then the base skill can become this. If you can avoid enemies and get them hit by the bombs, then you can kill every enemy in the game with basic bombs.
    • That all pales in comparison to the Fetus+Bra combo. Activate the bra and fling bombs from the proper distance for the entire duration, and almost every boss in the game (even Mom) can be killed before it even gets an attack off. It'll even take half the life off of the Cathedral boss if you have four power or so, rather less the mega bomb and/or maximum power. And unlike a lot of boss combos, it's also ridiculously effective in the levels too, since the fetus all but guarantees that the stun time is enough to dispatch every enemy in the room without risk once every three rooms.
    • It's not only useful in battles; you will essentially get a free secret room and super secret room each level if you take the time to look for them, which can have a massive impact depending on what they contain.
    • Dr. Fetus + Remote Detonator. Not only do you have an unlimited supply of bombs at your disposal, but the remote detonator gives you the ability to time your bombs' explosions; effectively negating the Dr. Fetus item's greatest downfall.
  • The Nail. When used, it gives a spirit heart, increases damage, and lets player walk over rocks among with the other benefits. This was even more broken in earlier versions, where it gave two spirit hearts.
  • Technology (piercing shots with unlimited range) + Chocolate Milk (charge shots) = Win (Northernlion approved).
  • Steam Sale (everything in shops half off) + dollar (maximized cash) = shops being very useful.
  • After the Halloween update, BRIMSTONE. It replaces your previous attack with an extremely powerful and wide beam which can fire through obstacles but must be charged beforehand. Properly mastered, you'll be a killing machine. Get damage powerups and it becomes even more awesome.
    • Rebirth made Brimstone even more absurd by allowing it to synergize with most tear modifiers. Now Inner Eye gives you a triple Brimstone beam (and Mutant Spider gives a quadruple beam), Spoon Bender makes the beam home in on enemies, and Tammy's Head obliterates everything in the room with a giant ten-way laser burst. And those are just the synergies that didn't exist in the original.
  • Whore of Babylon grants a Critical Status Buff if your character is reduced to one-half red heart or less (one full heart for Eve). This is normally situational, but if used by Blue Baby or The Lost, the effect is permanent because neither character is capable of gaining red hearts.
  • Mom's Knife + Mom's Contact. Mom's knife does rapid high-powered damage. Mom's contact has a chance of turning the target to stone per hit. Rapid hit + stone chance = stone enemy. Now, keep in mind Isaac can then just walk up to said immobile enemy with the knife, which will continue to do rapid damage plus turn them back to stone — so only enemies with backup will survive once that first stone hit kicks in.
  • Mom's Bottle of Pills + PHD. PHD removes all negative effect pills (damage, stat reduction), while the bottle lets you generate, at minimum, one pill every six rooms (with enemies). You may occasionally get neutral pills like Bombs Are Key, but (especially if you get it early) over time you're guaranteed to get a lot of tear/damage/range boosts, especially in the bigger levels. You can even use it with the Battery (plus the 9-Volt) to speed up your stat-increasing even more! If you're playing as Cain, you don't even need the PHD, since his innate Lucky Foot pill has the same effect.
  • The Prayer Card is the Game Breaker to end all Game Breakers. Once per six rooms, it allows you to create half of a Prayer/Eternal Heart. If you finish the stage with one of these, or manage to obtain a second one, you get a full heart container. To put it simply, if you're skilled, it lets you pull entirely new heart containers straight out of your ass, for free, every twelve rooms. It gets even more hideously broken if you manage to get the Battery with it, giving you the opportunity to give you a new heart container every two rooms. Naturally, this tends to make you able to completely buy out the Devil Room shops, making you an unstoppable force with insane power and health that doesn't even fit on the screen.
    • Taken Up to Eleven if you buy Guppy's Paw with those new heart containers. Guppy's Paw destroys one heart container in exchange for three soul/spirit hearts. Tough choice, right? Not if you already have 5 or 6 heart containers. Use up four or five of them, and that's an instant 12 or 15 spirit hearts!
  • Technology 2 (which shoots a laser that is weak as all hell but hits constantly). Because it hits very quickly, it will almost always activate items with on-hit properties such as Mom's Contact (which gives your shots a chance to freeze enemies), The Mulligan (which gives you a chance to spawn a kamikaze attack fly whenever you shoot an enemy), or the Common Cold (which gives shots a chance to poison).
    • It's even more overpowered with Polyphemus, which does ridiculous damage but sets tears to minimum. It's balanced, but with Technology 2 will down all bosses in seconds and one shot enemies.
  • Speaking of Polyphemus, it synergises insanely with Brimstone. Polybrim, as it is sometimes called, deals insane amounts of damage (that can be more than doubled via the Brimsnap glitchexplanation ) and its only draw, the long charging time, can be bypassed, at least for one shot, by charging it up before entering a room with enemies. With this combo, you can one-shot all enemies and most bosses within seconds.
    • Polyphemus also synergises well with any weapon where the tears stat matters little (Dr Fetus, Ipecac, Tech 2, Mom's Knife, etc)
  • Sacred Heart. It is basically a slightly weaker Polyphemus with a faster fire rate, plus the ability to home in on enemies. Upon taking it, Sacred Heart also instantly restores you to max health plus an additional soul heart. Unlike Polyphemus, taking Mutant Spider with Sacred Heart will not reduce Sacred Heart's damage, making Mutant Spider + Sacred Heart a very viable combo.
  • The Crystal Ball is yet another item which breaks the game wide open when combined with the battery. Even on its own, however, it's rather overpowered: once every six rooms, you may reveal the map (if you have not done so already) AND receive either a spirit heart or an extra tarot card. This makes the final few levels of the game much quicker.
  • Polyphemus+Mom's Knife, Northernlion approved (for those who didn't watch the video, it allowed him to take down Blue Baby in a few seconds).
  • The D6 allows you to reroll powerups. Combine this with the battery for half charge per room and a room with green bomb spitters to blow the doors open, and you can reroll (tediously) until you get what you want.
  • Scratch that, WotL brings in the D20 from Dungeons & Dragons fame. It rerolls every single pick up in the room, so you can reroll marginally useful items like pennies and half hearts and get pills, soul hearts, faith hearts, tarot and poker cards, nickels, dimes, the whole spectrum of trinkets and chests with several pickups inside, possibly even a powerup. Chances of getting great stuff are low per pickup, but then you go to an Arcade and pile up a huge stack of half hearts, keys, etc from the machines to polymorph at once. Good thing it has a 6 room recharge...
    • Not only that, but it can even reroll Troll Bombs. So basically, you just have to either use the Tower tarot card or when fighting War or Pride, you can use it to change all the Troll Bombs they summon into items.
  • Epic Fetus, which launches guided missiles almost as fast as Dr. Fetus launches unguided bombs. If you get this, the only thing likely to kill you other than the final boss is hilarious incompetence. Perhaps in recognition of the fact, the unlock image has the fetus giving the finger while missiles fall all around it.
    • Becomes even more powerful if you have A Pony. If you use the pony's charge attack, but not choose a direction, you will be completely invincible, so you can aim Epic Fetus's missiles with the mouse and clear any room with impunity.
    • Then get Strange Attractor, which causes enemies to be drawn to the target so they'll get hit by the blast.
  • The Scapular gives you a soul heart one per room once you are on the last half heart (normal) or, on ???, when you lose your last heart. Done right, you can use this to get lots of money from a heart donation machine by going to low health, exiting the room and going back after getting the extra soul heart, and use the machine twice, once in later levels, giving you another one. Exit, repeat. It also helps that it's basically regenerating health, allowing you more error. That ratio for error is small, but it's better than not being able to make error, but that part isn't really breaking.
  • The Ankh, which revives you as ???/Blue Baby if you die. In terms of Steam Achievements and game content, you ARE him. This nullifies half of the challenge of beating the game with him if you get the Ankh on a lucky run with another character and die on purpose. It also makes it entirely possible to unlock the Forget Me Now and the Rainbow Baby before obtaining the D6.
  • The X-Ray glasses. As noted above, they synergize with the battery for unlimited item charges. On their own, not only do they reveal secret room entrances, they also open them for you without needing bombs. Bombs are very important in the early game. They can also save you keys to enter a shop or item room if it happens to border a secret room.
  • Finding the Bloody Penny allows one to convert money drops into red hearts. Blood donation machines do the reverse, but can pay out nickels or dimes. In tandem, this can produce infinite money and consumable health for a floor. If found in an arcade, the combo can be exploited for infinite keys, bombs and Skatole. Even if the blood donation machine happens to pay out, it will drop the Blood Bag, which fills heart containers and gives an HP up, or the IV Bag, which acts as a portable, more reliable blood donation machine.
    • Especially if you consider that the Blood Bank's cooldown is slightly shorter than the Mercy Invincibility. Which means that, with a single half-heart (on the first 6 floors), you can use it twice and get 3-4 coins on average, which in turn give you 1-2 hearts on average. So, even without a slot machine, you can get infinite coins and hearts.
  • Dollar (max cash) + Money Is Power (boosts damage proportional to money total) = Total Annhilation.
  • Judas, if he finds Blood of the Martyr, will flatten the early game and have a distinct advantage through the final floors. His starting item, the Book of Belial, already stacks with Judas's inherent 4/3 damage multiplier, but with the Blood of the Martyr, the Book of Belial multiplies his damage by 1.5 in addition to its effects. Mitigated slightly because other 1.5 multipliers will cancel the active effects, it still can turn him into the ultimate Glass Cannon.
  • If you can, getting two or more "baby" items (Brother Bobby, Sister Maggy, etc...) allows for a ton of damage to be done, especially if you can get variations with special abilities.
  • The Guppy transformation. It requires touching any three of Guppy's Paw, Guppy's Head, Guppy's Tail, Guppy's Collar, Guppy's Hairball, and the Dead Cat items, meaning that you'll likely have to spend a lot of heart containers to transform unless you get very lucky with Red Chests. The transformation itself grants flight and causes every tear that hits to spawn a kamikaze fly. These flies deal twice as much damage as the player's tears, and one is spawned for ANY tear that hits. Add in any tear-firing familiars (or just a high fire rate), and just watch as anything before you gets cut down by an army of flies.
  • And then there's the literal Game-Breaker: Scapular+Habit+either reroll item. By bringing yourself to half of a red heart, running into a level hazard (such as a torch, some spikes, or a Curse Room door), and then leaving and re-entering the room (to reset Scapular), you can generate infinite rerolls. The usual outcome tends to be gigantic tears firing in four directions that home in on enemies, pierce them, and follow Isaac around to just destroy everything, with Guppy's flies on top of that. If the player lucks out and gets a God Room for the floor, the potential for firing bullets backwards is possible. Where it becomes literal is that you can generate so many items that if you pick up too many spacebar items the game just gives up and crashes.
  • In a mechanic example, Mom's Knife, Epic Fetus, and Brimstone, items which override most other forms of tears, can break the challenge maps by potentially replacing your worthless loadout with a far superior normal weapon. The remake gets around this with the Blindfolded mechanic present in some challenges, which completely disables tears.

    Rebirth 
  • Combining Mom's Knife + Mom's Eye + Loki's Horns + The Inner Eye + My Reflection + Tiny Planet could accurately be described as a "death blender", because this item combination (that Edmund McMillen says is so rare, you should probably go out and buy a lottery ticket after tearing through everything in your path) flings out three knives in each of the four cardinal directions (for a total of twelve knives) that quickly spin around you before returning. It has to be seen to be believed.
    • Technically, Mom's Eye isn't needed at all for this combination (and in fact is supplanted by Loki's Horns, making it useless). If you had the Quad Shot, however...
  • One of the new items is Monstro's Lung. By itself, it's a decent upgrade, giving you a charged vomit attack like that of its namesake. And then you get the IPECAC. A combination of this with being able to fire multiple shots at once pretty much guarantees a One-Hit Kill on most enemies. And then you get Cricket's Body which causes the tears to split for even more explosions, then Fire Mind so each explosion leaves behind a wall of fire.
    • Another overpowered Monstro's Lung combo is Chocolate Milk. Basically, Chocolate Milk is a different type of charge item, that lets you shoot tiny shots at lower damage or fully charge for a bigger, more powerful shot. Combining it with Monstro's Lung makes each shot a full power Chocolate Milk shot at no extra charge time. If you get Mutant Spider, which usually gives you a quad shot, your charge time will be extended to a ludicrous amount, but it adds even more projectiles! And if you want, go ahead and add the aforementioned Ipecac. Mega Satan doesn't stand a chance.
  • Azazel puts Cain to shame for the sheer favorability of his starting loadout. In exchange for no bombs or keys, you start with a short-range Brimstone and flight, a combo which utterly dominates all but a small selection of enemies and bosses in the early levels. If you happen upon Tiny Planet or the Ludovico Technique, you've practically beaten that run, and both of these can be found in the first floor. The only thing working against Azazel is his short range, and that's easily overcome with just a little skill. If you're looking to unlock all the levels so you can play the rest of the characters at your leisure, Azazel's the go-to character.
    • For a time, Afterbirth increased the charge time of his Brimstone and lowered its power by 30%. But this was quickly reverted in an update that arrived 4 days later.
  • Dark Bum converts every one-and-a-half red hearts he picks up into a soul heart, though he may occasionally toss out a spider (hostile or friendly), instead. Considering that there are a ton of Red Heart drops throughout the game, this makes getting a full set of soul hearts trivially easy for anyone remotely good at dodging. This makes buying out Devil Rooms that much easier, and every character save the Lost benefits from using him. He's especially good when used by Eve (whose Critical Status Buff isn't negated by Soul Hearts) and ???/Blue Baby, neither of whom have much use for red hearts otherwise. He used to be even more broken, dropping hearts at a 1:1 ratio with no downside.
  • And then there's the Gnawed Leaf. It makes Isaac immune to all damage when he stands still for two seconds, but that immunity goes away when he moves or shoots a tear. If you couple this with an item that does damage by itself without any player input (of which there are quite a few), it makes it impossible to lose under most circumstances. Especially if you have a level 3 or 4 Meat Boy or Bandage Girl or the Pinked Shears. Then, as long as no enemy is behind an obstacle, you just sit back and let Meat Boy, Bandage Girl, or Isaac's body kill everything. Even with just a damaging orbital it can trivialize a lot of rooms. And if you get Daddy Longlegs together with this, every room in the game (without a Host in it at least) turns into "Isaac Wins by Doing Absolutely Nothing".
  • The Broken Remote trinket turns the effect of your spacebar item into a teleport. Combine with any zero-charge spacebar item for unlimited teleports. With patience, this combination guarantees access to every room visible on the map, including each floor's shop, Item Room, rarer rooms like the Dice Room/Library/Bedroom... and removes the need to spend keys and bombs to get there. That you get to escape/skip problematic rooms is a nice bonus.
  • The Ludovico Technique. On its face, it just turns your normal tears into a single, player-controlled permanent tear, which is useful but has its disadvantages. Then you mix it with Brimstone. Instead of a mere tear, you get a giant ring of pure death that you can sweep across the screen to destroy all in your path. The same result can also be found by combining with Technology — a crackling beam of energy turns into a circle of desolation. Then combine it with the Lost Contact, which makes your tears destroy enemies bullets. Congratulations, the enemy is now incapable of shooting you. Even Mega Satan can barely manage to sneak a bullet or two through. It does not, however, stop flame attacks. For even more hilarity, combine the normally useless Strange Attractor and your single bullet becomes an enemy-sucking black hole.
    • Add Parasite to Ludovico and Strange Attractor and you'll be creating multiple gravity wells that will pull the enemy around so fast that they will appear to be torn apart not from damage but from cycling through quantum states until you observe them dead and collapse the waveform as a bloodstain on the floor.
  • Pyromaniac causes explosions to heal you. Combine with an endless supply of explosions, such as IPECAC or either Fetus, and at least two heart containers, and enjoy the free win as you can infinitely heal from your own shots. Bob's Brain, normally a Scrappy Weapon, also becomes much safer and more useful. Lacking any of these, it still turns every explosive-firing enemy and every bomb into a source of healing.
    • Even better: Combine it with Kamikaze! Once you do, congratulations — you now have a means of gaining free health on demand that's also an offensive maneuver. Victory by this point is pretty much a given.
    • Many non-bullet attacks by end-game bosses count as explosions. In other words, both Mom's/Satan's stomping attacks and Mega Satan's hand smashes will heal you if you have a Pyromaniac. And yes, this includes the constant stomping you get from picking up the Broken Shovel, which makes unlocking the Forgotten much easier.
  • The Blank Card allows you to use the effect of whatever card or rune you're currently carrying (or, if you have multiples, whichever is on top) with a four-room charge. On its face, this is pretty useful, since cards like the Hierophant are only balanced by the fact that you can only use them once. What makes it really broken is the fact that items which enhance card effects and active item effects stack, so a combination of the Tarot Cloth and the Car Battery can potentially quadruple the effects of the cards you collect. There are few cards or runes you can't abuse with this method. This was nerfed severely in Repentance, splitting the rune-copying effect to a separate item and changing the charge based on the card/rune used, making a lot of these combos less practical in some cases, and even better in others.
    • The Hierophant: Doubled Book of Revelations on a shorter charge and without the drawback of changing boss spawns.
    • Strength: A damage and size boost every four rooms. Excellent for the Forgotten, especially in Greed mode.
    • The Sun: a full heal, room nuke and full level map every four rooms. Combined with the Habit and at least five heart containers, you cannot lose, as you'll have a full heal always available before you die. Add the Wafer and not only does it cut down the requirement to three hearts, but now it can be any three hearts if you have the Hierophant.
    • 2 of Diamonds: infinite money and thus items in Greed Mode, as long as you can buy a battery and have more than 11 coins.
    • Joker: Guaranteed Angel/Devil Room every floor.
    • Chaos Card: Guaranteed boss defeat every time (provided that you don't miss). It even works on Ultra Greed, if you use the item and the card.
    • Era Walk: Stop Watch effect for the current room.
    • Credit Card: Free Shop and Devil Room items. In Greed Mode, provided there's a reroll machine, you can clear the shop multiple times.
    • Suicide King (+ 9 Lives): Absolute shitloads of free pickups and items. Just make sure to find some way to compensate for the loss of health. If you have Guppy's Collar, each use has a 50% chance not to consume one of your extra lives.
    • Rune of Jera + a single battery consumable: Infinite pickup duplication.
    • Rune of Perthro: Better D6.
    • Rune of Dagaz: Better Book of Revelations (but not as good as Blank Card + The Hierophant) that removes curses.
    • Black Rune: Faster-charging Void that also converts active items and damages enemies.
  • Guppy's still in, and even more powerful. Flying has even more utility now, especially in the Womb, and you can now buff the damage of Guppy's flies even further by finding the Hive Mind item. It's also much easier to become Guppy without having to invest a lot of heart containers, as red chests are more abundant and there are now five Guppy pieces (only one of which eats all of your heart containers). What makes Guppy even crazier in Rebirth is that you can now build an army of flies up (usually via piercing tears) and actually keep them between rooms instead of being reduced to five flies. The results of said army hitting a boss in the face tends to end poorly for the boss.
    • Guppy also has a variant in the much easier-to-find Beelzebub. By finding three fly items (of which there are 18 post-DLC, 15 of which are Treasure Room items), you automatically become Beelzebub, a flying bug man who converts almost all hostile flies into fly familiars.
  • Some of the most powerful items include the extraordinarily difficult unlocks for the game's resident Secret Character, THE LOST. It requires winning with a One-Hit-Point Wonder through the path without a real 11th-Hour Superpower to assist you, but the rewards are definitely worth the effort:
    • The Soul. What does it do? Bullet Dodges You in a game where many of the final bosses employ Bullet Hell.
    • Unlocking the Soul also unlocks The Mind, which combines all three shop-sold mapping items in a single Treasure Room or Angel Room item.
    • Isaac's Heart. This spawns a heart familiar that takes damage for you while making your character Nigh-Invulnerable. Curse Rooms? Free access to them. Blood Donation Machines? Infinite money with no cost whatsoever Explanation . Devil Beggars? Free items, as well as a few neat pickups. Items that require touching enemies, such as Midas' Touch? Abuse it as much as you like! Blood Rights? A guaranteed clear for every room and boss, as you can freely abuse it with no health cost. The only downside is that every enemy and boss targets the heart instead of you, but as long as you can protect it, you've gotten yourself one hell of an item.
    • The -0- Baby, which is a co-op baby that is completely invincible.
    • The very last one of these, and the hardest to unlock, is the Godhead. This gives you homing tears with an aura that damages anything within it, along with increasing the base damage. Combine this with items that increase the size of tears to increase the radius of the damaging aura and thus damage enemies even further.
  • Contract From Below is a Devil Room item that duplicates every drop you get for clearing a room. Humbling Bundle turns every red heart, bomb, key, and penny into "1 + 1 Free" versions. Having them both means that whenever you would have gotten any of those items for clearing a room, you now get four!
  • Technology + any homing shot item = infinite-range homing laser. Even with the starting damage stats, it's useful. If you've found even one or two damage upgrades, it's very powerful. With several damage upgrades and/or evasion properties like speed or flight so that you can fire from safety? Godlike.
  • Cursed Eye allows you to shoot 4 charged tears, but the fact that it teleports you away if you're hit while charging it outweighs the benefits. Take it after taking Chocolate Milk (normal charged shots), and the game will combine the 4 tears into a single giant one, with quadruple damage and quadruple charge bonuses.
  • The Converter is an active item that allows you to convert 2 Soul/Sin Hearts into one permanent heart container. As you would imagine, it combos supremely well with Guppy's Paw, and by switching between the two, you can turn one permanent heart container into as many as 11, making even the Dark Bum seem petty in comparison. It helps that the common place where you can find the converter is the shop.
  • In certain situations, the Holy Mantle isn't just a game breaker, it's a game maker. Commonly found in Treasure Rooms and Angel Rooms, the Mantle protects you from one hit per room. It doesn't count as damage, making the "____ Boy" achievements for completing floors without damage much easier. You can also use Curse Rooms for free, and makes Devil Rooms more likely to appear, as you're more likely to play well. And then there's its compatibility with The Lost, who is a One-Hit-Point Wonder and dies instantly if he takes damage. Meaning that, for most players, finding the Holy Mantle (and to a lesser extent, the Dead Cat, which still applies 9 lives to the character but resets the room if you die), often by way of constant resetting and/or hoping for an Angel Room to spawn, is the only way they have a chance of winning.
  • The Wafer, in addition to reducing damage on later floors to half a heart instead of a full heart every time, reduces Sharp Plug's health cost to half of a heart. Outside of the obvious infinite health combos, this combo has pretty much replaced Habit+Scapular (even though that combo is still effective if tedious) as the combo of choice for item pool clearing breaks.
  • Soy Milk is a kinda bad item at first. It gives you a huge tear rate, but piddling damage. But if you get Libra? Then the game is over, because all of your stats get balanced with your high tear rate, giving you huge damage, as well as everything else, including a still high tear rate. Also, feel free to get Guppy if you want. Omgarrett shows off this broken combo here.
    • From there, try adding 20/20, the Inner Eye, or the Mutant Spider... or try adding them all together. Libra will keep your firing rate from decreasing, letting you continue to machine-gun enemies like no tomorrow, while adding more tears to each shot.
  • Sad Bombs plus Rubber Cement plus Scythes results in bombs that produce piercing, bouncing scythe projectiles. Add some damage onto it, like, say, Money Equals Power and the Lump of Coal, and you could potentially have giant, bouncing scythes being produced as bomb fragments that wipe whole rooms. This also works with Tammy's Head.
    • Or combine Sad Bombs with Brimstone. Add some damage powerups, Mr. Mega, and every bomb becomes a room-wiping Brimstone nuke.
  • Speaking of Tammy's Head, Rebirth has made it absolutely absurd when stacked with Tear effects. Parasite? Produces more sub-teardrops, and once again, stacks with Rubber Cement to make bouncing, splitting tears. And yes, you can make them be homing, piercing, bouncing, splitting tears. Brimstone? Produces an 8-way laser of death (that stacks with Homing Tears effect). All that, and Tammy's Head recharges once per room. This combo can even break the otherwise annoying Blindfolded Challenges, which shut off normal tears.
    • And when you stack Tammy's Head, Brimstone, and the Tiny Planet, you get this. In fact, the current fastest run of Rebirth is an Eden seed that begins with the Tammy's Head+Brimstone combo and finds Tiny Planet (and homing) later in the run.
  • A more minor one: Undefined, the item gained by completing Boss Rush with Eden. Yes, its name is a reference to the 'Undefined' item that would spawn in the original Binding of Isaac once you had exhausted everything in a particular item pool. Its effect? Teleports you either to the Treasure Room, Secret Room, Super Secret Room, or the goddamn I Am Error room! All this with just a 6 room charge, too! Long story short: It does its namesake justice, as you can easily obtain lots of money, save on keys, and get free powerups with it. (And if you get to the Chest with it? You can repeatedly reset the floor by going to the I Am Error room, getting more and more items and making your Isaac the most broken character ever made, with easily over five times the amount of items you'd get in a single run!) Oh, and it spawns in the regular Treasure Room, as well.
  • The Stop Watch. In Rebirth, it causes all enemies and their bullets get the slowdown effect. For the entire run. You have to pump 999 coins into the shop donation machine over many playthroughs to unlock it, but once unlocked, it becomes part of the shop item rotation. The slowdown isn't just a time effect, either. Enemy bullets have a duration, so their range is drastically reduced. Enemy charge attacks likewise wear out almost instantly, giving them no charge distance. The only thing you have to watch out for is some enemy familiars (the Ovum of Blighted Ovum, the Mask of Mask and Heart if the Heart is alive), as they aren't affected by the slowdown. Tracking bullets may also chase you down unexpectedly. Afterbirth nerfed it by making it an on-hit effect that only lasts a single room, which is less useful but still pretty gamebreaking, especially if you have the Holy Mantle. Repentance made the effect permanent again, but significantly reduced the slow effect.
  • The "Magic Fingers" item allows you to do room-wide damage by spending coins, and has no limit to its use or cooldown, essentially making it a Blood Rights only with money instead of life. It gets gamebreaking because the damage it does scales with Isaac's damage, which can make it absurdly powerful if you get high damage/low rate of fire items. As long as you have enough money to pay for it, which is easy enough to come by, you can stroll through most of the game with the press of the button. Even if you have to penny pinch, it can at least let you get through the bosses with ease.
  • Most people will tell you that Blood Rights is a terrible item due to being fueled by your health. But combine it with Taurus and once per room, you can spam it incessantly for the duration of your invulnerability. Isaac's Heart is even better, allowing unlimited use since you are technically invulnerable. Three uses will kill any mook that isn't invincible somehow. Guaranteed to utterly tear apart all but the most resilient bosses, but even then they will only be hanging by a thread after this treatment. The only things this won't kill quickly are Hush and Ultra Greed, and even then you can tap them to death while focusing on dodging, not to mention the fact that their mooks die instantly.
  • The Crying Detonator (Sad Bombs + Bob's Brain + Rubber Cement + Ipecac) Combo. On the upside, everything is blowing up via either normal bombs, Bob's Brain, or you own tears, scattering all over the place and bouncing into enemy faces and poisoning them on the spot. On the downside, however, you're constantly on the move away from your own exploding tears and Bob's Brain, since they can also damage you. This Game-Breaker uses a balance of being strong enough to demolish bosses and enemies and being able to withstand your own blast. The effort's negated, however, if one gets the Pyromaniac item, as Isaac can get health from all explosions, including his own barf bombs!
  • Anti-Gravity. On the surface, it sets tears that stay put until you release the attack button, effectively making a Delayed Attack. The Gamebreaking comes when mixed with either Monstro's Lung (Delayed Charged Attacks), or Brimstone. What makes Gravity Brimstone so overpowered is how it is fired: timed Brimstone Orbs that fires in the targeted direction. While it is difficult to aim, it allows you to re-position yourself and fire another. Using Mutant Spider or Inner Eye allows not only more Brimstone shots upon firing, but a larger Orb Radius to the point you can damage enemies with the orb itself.
  • Ipecac has become the damage combo monster that Wrath of the Lamb's Polyphemus once was:
    • Adding Monstro's Lung turns the many bullets fired into Ipecac bombs, which is about as devastating as it sounds by blowing up a wide area and deals massive damage to bosses (again, provided you don't blow yourself up first).
    • Adding Magic Fingers allows you to clear almost every room until the Womb with a single cent, and considering that you can use Ipecac to bomb the shop's donation machine for as much money as desired, it's not too difficult to clear an entire run with just Magic Fingers alone.
    • Adding Epic Fetus (or the airstrike from Doctor's Remote) results in far and away the strongest attack in the game. If you add on another damage multiplier such as Cricket's Head or Magic Mush, it's capable of taking out It Lives in a single shot!
    • Combines with Soy Milk to become a rapid-fire explosive bullet stream similar to a minigun firing phosphorous bullets.
    • Combines with Infestation 2 to spawn blue spiders with every enemy destroyed. Most bosses in the game can be beaten by doing nothing as the boss gets swarmed by twenty-plus spiders capable of two-shotting them.
    • Combines with Dr. Fetus to produce bombs resembling the standard poison-bomb upgrade. In addition to poisoning enemies, they explode instantly upon coming into contact with one, and can't hurt youwarning . Finally, the bombs from Dr. Fetus deal 3 times your current tear damage, or, with Afterbirth, 5 times your damage plus a flat 30. Ipecac bombs increase tear damage by +40. Every bomb now deals a minimum of 120-230 damage (for reference, Mom has 645). Should you somehow also get Soy Milk in addition, anything more than a brief tap of the fire button will cause your bombs to explode against one another, propelling you forward at five explosions per second.
  • Chocolate Milk, now with all of the nasty bugs taken out, is another combo monster. Try adding Death's Touch (gives a large amount of damage and turns tears into much larger piercing scythes) and some more big damage items, such as Polyphemus, and soon your fully-charged tears will take up half of a standard room, instantly eradicating most non-boss rooms. If you feel like mashing instead, get Guppy or the Mulligan and let the flies do the killing.
  • The literal Game Breaker this time is Sad Bombs plus Godhead, provided you have a lot of bombs. Letting enough of them go at once (possible by laying one down, leaving and re-entering the room, laying a bomb, rinse and repeat) is currently the only way to crash the game outside of the True Final Boss.
  • What happens when you take two game breakers and mix them together? You get Mom's Knife + Brimstone, which is Mom's Knife followed by a spray of Mom's Knives across the screen.
  • Although it's unlikely to get, here's an OP combo. Polyphemus (big tears with high damage that can pierce through enemies that they kill) + 20/20 (double shot) + Cursed Eye (teleport out of room if you're hit while charging, but you can get up to 12 shots with 20/20) + Sacred Heart (more damage, in addition to homing tears) + Rubber Cement (if your tears miss, they can bounce back) + Parasite (when your tears hit an enemy, they split into two smaller tears that have all the aforementioned abilities, including more splitting) = An Isaac to be avoided, or you're screwed.
  • Combining The Parasite and Cricket's Body, which both cause tears to split on hitting an enemy, can cause some absurd damage very quickly. Add several damage-ups such as Meat!, and homing shots from Spoon Bender, and your split shots will curve in onto enemies and shred them in seconds.
  • The Lost Contact is decent by itself, causing your tears to destroy enemy tears (or other sorts of bullets). The drawback is that your tears are destroyed, too, so you have to shoot through any bullets to actually land a hit. But that's not the case if you get an item which grants piercing. With both effects, your tears stop bullets and keep right on going. With a high enough tear stat, nothing in the game will be capable of shooting you with regular bullets. This includes Bullet Hell bosses, such that you can conceivably completely lock down their tear shots before they can even fire them.
  • The D4 and D100 (and to a lesser extent the dice rooms) allows you to reroll the items you currently have. Is your run bad or even so-so? Just reroll your run! Is what you got not that great? Just reroll away until you get something that is! Even the worst-case scenario of emptying the item pools isn't that bad considering that the result is getting 12 full red hearts, making the dice powerful healing items. Even better, especially with Afterbirth, is that all the items you get through rerolling count toward transformations, meaning that you'll at the very least get the Lord of the Flies transformation, and all transformations are kept regardless of rerolling. Also, if your reroll gives you an item that gives you consumables, like Pyro or Libra, you get to keep those too.
  • Death's Touch + Godhead + Proptosis + several damage ups = giant scythes with auras as large as the screen, both of which will kill regular enemies the instant they expose their hitbox and most bosses just a hair later. Even bosses with damage reduction won't last long.
  • Using Isaac's Tears with Brimstone + Chocolate Milk gives you absolutely gigantic (i.e. as big as the screen or larger) tears that cause ridiculous amounts of lag but utterly shred anything they touch, easily one-shotting almost every common enemy and even most bosses in less than a second. Combined with Isaac's Tears's unique charge method of holding down one of the fire buttons, this gives you potentially the closest thing Rebirth has to a "win the game instantly" button.

    Afterbirth 
  • Placebo, a new spacebar item which acts as a Blank Card for pills. While most pills are not as strong as cards/runes are, there are still some extremely beneficial uses to Placebo. Like the Blank Card, it was nerfed in Repentance, changing the charge time based on the pill.
    • Placebo + Full Health = Refills all red heart containers every four rooms.
    • Placebo + Health Up = Pulls a new heart container out of your ass every four rooms, which is faster than even the Prayer Card.
    • Placebo + Tears Up = Depending on how early you get it, you won't even need tear items.
    • Placebo + Speed Up = Move so fast it's actually detrimental.
    • Placebo + Luck Up = Becomes one of the best luck-increasing items in the game, increasing the stat every four rooms.
    • Placebo + Lemon Party = Significantly stronger Lemon Mishap which can cover a huge portion of the room.
    • Placebo + Powerpill = Gamekid with a 4-room recharge rather than 6.
    • Placebo + I'm Drowsy = Stopwatch effect for the current room.
    • Placebo + Pretty Fly = Creates a new fly orbital every four rooms, to a maximum of three, which can easily prevent enemy projectiles from damaging you.
    • Placebo + Balls of Steel = Much stronger Book of Revelations which doesn't force a Horseman to appear as the floor's boss.
    • Placebo + One Makes You Larger = Useful for the Forgotten, as it allows you to maximize your melee range. Just don't go overboard.
    • Placebo + 48 Hour Energy = Infinite Lil' Batteries and therefore infinite charges for Placebo. Combine with other pills on the floor (or Little Baggy to hold multiple pills at once), and you can use their effects endlessly.
  • Lilith's Box of Friends allows her to double all the familiars currently in her possession every four rooms. Combine this with charge modifiers like the 9 Volt and she becomes dangerous. Stick her in wave-type fights like Greed Mode or the boss rush and she is an absolute monster. Since you get one part of the meter charged at the beginning of each wave, you can keep doubling your familiars until the end of the fight. Add on to that whatever tear modifiers she has and you effectively have numerous copies of yourself all fighting at once.
    • With enough Incubi and a high enough fire rate, Strange Attractor can make it impossible for enemies to move away from the wave of tears. This can make things like boss rush ridiculously easy since each wave gives you a full Box of Friend's charge.
    • Prior to Afterbirth, the achievements for creating Meat Boy and Bandage Girl were notoriously difficult due to both the astronomically low chances of getting four horsemen (and not having Conquest replace one if he's been unlocked) and the relative difficulty of getting a "breaking run". Spoiler  With Lilith and her Box of Friends, ONE Cube of Meat or Ball of Bandages is all you need. Getting either a good amount of batteries, getting to the boss rush with at least one, or being in Greed mode and the achievement is pretty much guaranteed.
    • There's also the Car Battery passive item, which doubles the effect of your spacebar item. Give one to Lilith, stick her in Greed Mode or Boss Rush and... you get the idea.
  • Speaking of Lilith, the Incubus familiar itself qualifies. It is a familiar that almost completely copies your tear stats and effects, having one on a character without a blindfold will basically give you 20/20, except it can also copy that.
  • Sad Bombs now synergize with Brimstone, and the results are just as spectacularly destructive as you would expect. Combine with Scatter Bombs, which cause your bombs to explode into more bombs, for instant Beam Spam that annihilates everything in the room. And unlike Tammy's Head, this can be used multiple times per room as long as you have bombs to spare.
    • This also includes Dr. Fetus; the result is an attack that takes a hilariously long time to charge, but then instantly explodes into a ten-way brimstone laser.
  • The D7 used to be this when it was first introduced. It works somewhat like the VS Seeker in Pokémon, allowing you to 'restart' a room that originally contained enemies and reap rewards for clearing it. The problem is, back then, the item recharged the instant you cleared the room, allowing you to repeat rooms and obtain rewards indefinitely. What's more, the rewards you could get from clearing the room could change with every use, meaning that patient players could have obtained well over the amount of keys, bombs, pills, coins, and even chests that they would have ever needed, without even having to leave the room. This proved to be gamebreaking enough that the D7 was eventually nerfed to a three-room charge, although infinite farming is still possible with the 9-Volt/AAA Battery and a three- or four-part room.
  • Restock and two Steam Sales. Originally, getting a second Steam Sale was a moot point, as it usually came too late to be useful and it didn't stack anyway. Now it does, allowing you to buy items for free. Restock, meanwhile, causes shop inventory to instantly restock when you purchase something, with no upper limit. You can theoretically buy out not only the shop, but every other item pool in the game. It becomes a literal game breaker if you buy Missing No. by accident, or any other item that rerolls your items.
    • It gets even more ridiculous when you go into Blue Womb. Especially if Chaos and Restock is being sold. With the potential to get almost every single item from every pool possible, it makes even The Hush, a boss that scales with your damage, too easy as it gets shredded in under 10 seconds by every item you've gotten from the shop earlier!
    • However this was nerfed in Repentance. See here.
  • Take a blank card and get a "? Card" and use the blank card in a shop. It will pull up a random passive or active item. It's rare to find both together, but it can be worth it, especially with something like Car Battery. Needs more testing to see if it depends on the room that the combo is used in.
  • The Refresh machine has a chance to reroll all the items in a room if you give it a coin. It is guaranteed to do the same if you bomb it. With the Fetus items or Ipecac, you can reroll until it explodes at no cost. This is especially helpful in Greed mode, where you have the Restock item already so the shop never runs out. Just keep bombing it until something you want comes up.
  • Tech X turns your tears into laser rings, similar to the one created by Technology + Ludovico Technique, except fired like regular tears instead of guided manually and which grow larger with a longer charge. This is pretty awesome by itself, but they synergize insanely well with virtually all damage upgrades. For example, combine it with Dr. Fetus, which lets you fire bombs with laser rings around them. Due to the large damage increase from Dr. Fetus, the laser ring alone deals massive amounts of damage. If something manages to survive that, well, there's still the actual bomb explosion. Even Ultra Greed goes down relatively easily to this combo, since the laser-ring-bombs tend to destroy his giant coins nigh-instantly.
  • Continuum is pretty mundane by itself. It gives your tears a wrap-around effect that causes them to pass through the wall and emerge from the opposite wall. Useful, especially if you need to kill something dangerous without much risk, but not a big game changer. However, get Tech X or some other long-range attack with piercing and you now have a wrap-around weapon that just keeps moving and doesn't stop till the range runs out. Enemies take obscene damage as they're hit with barrages of tears.
  • Sack Head is essentially a Contract From Below on steroids, as it gives you far more loot sack drops than you could ever need. Said loot sacks will usually yield around three consumables each time one is opened, and with the massive boost in drop rate from Sack Head, you'll rarely be hurting for consumables. The sacks will even drop one-time use items like tarot cards and pills, and also batteries to recharge your space bar item, making them even more useful.
    • Adding the Sack to the D20 can break the game, as the possibility to spawn chests, which drop sacks, which drop even more sacks, can just spawn hilarious amounts of items. The chance of a battery spawning can also chain the combo indefinitely.
  • Bomber Boy causes your bombs to explode in the Bomberman cross shape, which comes with its upsides and disadvantages. The catch is that this is achieved by making the bomb create multiple explosions in a cross formation, which has obvious synergies with bomb modifiers. Glitter Bombs? Multiple pickups from a single bomb, including more bombs. Sad Bombs? A ridiculously large tear burst. Butt Bombs? Massive damage to everything in the room. And so on and so forth.
  • On their own, Glitter Bombs are useful but not too broken: each time one of your bombs explodes, it has a chance to drop a random pickup or trinket. But combine it with a golden bomb or either Fetus item, and congratulations—you now have an infinite pickup generator. With enough time, Luck, and patience, you can generate infinite health, infinite keys, infinite money (invaluable for Greed Mode!), infinite trinkets, and the list goes on. Combine it with items that cause your bombs to split, such as The Parasite + Dr. Fetus or Scatter Bombs, and it's possible to fill the entire room with goodies.
  • Curse of the Tower causes bombs to spawn around the room whenever the player is struck. Normally, this is an extremely risky upgrade, but when combined with Pyromaniac, it means that every time you get hit, you explode most of the screen and heal yourself. Since the blasts of multiple bombs will even heal multiple full hearts, this renders anyone with more than a couple red hearts invincible when played with the slightest skill.
    • Also, if you have the scissor Trinket that safely transforms Troll Bombs into regular bombs, you'll have so many bombs you won't know what to do with them. Add the D20 and you'll be able to get a ton of items.
  • Mega Blast, an unlockable activated item which is Purposely Overpowered like the Stopwatch. Using it results in you firing a massive Brimstone laser which has incredibly high damage and persists between rooms, lasting a grand total of fifteen seconds! Because of how insane the item is, it's the only one in the entire game with a 12-room charge and also the only one that isn't fully charged by picking up a Lil Battery.
  • The Car Battery doubles the effect of your spacebar item, which makes several of the already gamebreaking Blank Card and Placebo combinations absolutely ridiculous. You want four soul hearts every few rooms?
    • And if you have the Habit and the Car Battery, the Blank Card + Hierophant or Placebo + Balls of Steel effectively makes you immortal, since by the time you go through your four soul hearts, you'll be ready to use the item again.
  • The Glowing Hour Glass. When used, this spacebar item sends you back in time one room, resetting your health and pick-ups. This alone has some pretty useful applications; for instance, Curse of the Blind becomes trivial as you can simply reset if you get a bad item, shrugging off accidental damage, and so on. The real kicker is that it also fixes a jammed donation machine without affecting the counter. Find a shop with a battery pickup, and you can potentially max out the donation machine in one sitting.
    • Glowing Hour Glass + ? Card (has the same effect as your current spacebar item) = infinite usage, as you go back to before you used the ? Card. The same is true if you have the 48 Hour Energy pill or the Habit item, which both recharge it at the cost of a resource which will be reset. You can try the same boss a dozen times in a row until you beat it, if necessary.
  • For your consideration: Sad Bombs cause 8 tears to fly out in the cardinal directions from every bomb you use. Proptosis causes your tears to do huge damage on close-range targets, but die off farther away. Bomber Boy causes your explosions to detonate in a huge cross shape, similar to the bombs from Bomberman. Bobby-Bomb causes your bombs to home in on enemies. Mix these together (adding a damage boost for optimum effect), and boss fights are no longer an issue. Forget wiping out rooms full of enemies; if used properly, one of these bombs can one-shot most bosses, up to and including Mom's Heart.
  • Super Bum. If the Random Number God gives you his blessings so that you get Bum Friend, Key Bum, and Dark Bum in a single run, they do a Fusion Dance into a bum that picks up all kinds of consumables and pays out nearly instantly with way more than what went in. Pick up a key? He gives you three golden chests. A half red heart? Pays out with anywhere from two to six soul/demon hearts. And because he still can drop keys, bombs, and red hearts, it can result in an infinite cycle of pickups that will eventually flood the room, making you more or less unkillable if he happens to pay out with soul hearts. Combine it with an item that increases your resources like Contract from Below or Sack Head, and it's entirely possible he'll crash the game.
  • No. 2 is a finicky but potentially very useful item. Its primary effect causes you to drop poop bombs randomly while firing tears, causing minor roomwide damage. Thing is, this synergizes with other bomb types, and No. 2 is effectively infinite bombs at a fairly reliable pace (one every five seconds or so at the standard firing rate). Tack on Scatter Bombs, for example, and a single poop bomb detonates five times, turning it into a free, reusable Necronomicon that comes at minimal risk to yourself as long as you're attentive. There's also the more mundane benefit of being able to blow up anything whenever you want at no cost but a bit of time.
  • On the note of free Necronomicon, Satanic Bible + Sharp Plug. Normally, Sharp Plug costs 2 hearts to use and it automatically refills your current active item if it has no charges, but the effect won't overflow from soul hearts to red hearts. This means simply use Satanic Bible, Activate Sharp Plug, and it will destroy the black heart and activate room-wide damage but not touch Isaac's red health.
  • Glass Cannon is generally very risky to use, as it fires a single huge high-damage shot at the cost of making you one hit away from death. Picking it up with The Lost, however, basically provides a giant deathball at no cost. Glass Cannon also synergises with items you've obtained such as Scorpio or Continuum, and has a charge rate that's time-based, so finding this on a Lost run can easily guarantee you a victory if you're savvy enough with it.
  • For some reason, using the Glowing Hourglass while holding the Liberty Cap will eventually start stacking the size downs you get from Liberty Cap until you can't see your character.
  • In the original, Crack the Sky was lumped in Awesome, but Impractical, as the beams summoned by the item don't hit enemies with any degree of accuracy, and the recharge time buff in Rebirth didn't make any real difference. Come Afterbirth, however, the item was buffed again so that the beams tend to target enemies directly, meaning that instagibbing a boss with the white feather is now much, much more likely. Grab it early enough, and even troublesome bosses like The Haunt and Rag Man tend to become non-issues under concentrated Beam Spam, and its damage and charge time remain respectable enough throughout the game to be worth holding on to.
  • The D20 is back with a vengeance in Greed Mode. The coins that spawn with each wave are intended to give you a means to purchase items and consumables from the shop to become stronger... but nowhere does it say that you're not allowed to reroll them into consumables and chests with the D20. Given that the Greed Mode shop always sells keys, you can easily buy as many keys as you need to pop open all the chests you're getting, allowing you to reap several times your money's worth in rewards, ranging from piles of pickups to pedestal items. Even better if the shop happens to contain a battery pickup, as a single roll of the D20 will almost always refund the cash you spent on the battery and then some, allowing you to just keep rerolling and building up an absurd collection of items. It's not unheard of to build up an Isaac that can kill Ultra Greed in seconds with this method.
  • The Swallowed Penny is normally an okay-ish item, spitting out a coin if you take damage. With the Keeper, whose health is coins, it grants virtual immortality. So long as you don't take a second hit before grabbing the coin, you will replenish your health endlessly.
  • Another single item, Teleport 2.0, can be this. Similar to the regular Teleport item, it's a spacebar item that teleports you upon use. However, Teleport 2.0 is guaranteed to take you to a room you haven't visited. This doesn't seem very exciting, until you've visited every room on a floor, in which case it will take you to the secret room, then the super secret room. If you've already visited THOSE, it will take you to the floor's devil/angel room, even if you missed the chance to get it from the boss fight. And if you've already visited that? You get a free trip to the "I Am Error" room, which tends to contain some good, free stuff. Essentially, provided you can charge up the item enough, you're guaranteed a devil/angel room, and the I Am Error room on every floor you have the item.
  • Epic Fetus + the Conjoined transformation + 20:20 + Strange Attractor = a barrage of six obscenely powerful missiles at a time that draws enemies towards ground zero. Any regular room and almost any boss that doesn't have damage reduction will be cleared out in seconds. Unlikely to happen without a ton of rerolls, but worth it.
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    Afterbirth+ 
  • One of the new characters, Apollyon, starts with Void, an item that allows you to convert useless passive items into stat boosts. Where it shines, however, is its ability to permanently absorb the effects of active items, with the exception of those that can only be used once. Mega Blast? Now a six-room charge. Delirious? A friendly boss every six rooms. You can stack together the Satanic Bible, Prayer Card, and Book of Revelations for five more hearts every twelve rooms. Throw in the Nail for even more health. There's very few active items not worth taking.
    • Add the Placebo + 48 Hour Energy combo. You can now infinitely use any spacebar item in the game.
      • Libraries, Boss Rush rooms, Angel Rooms and some of the new double-item Treasure Rooms become a cornucopia, since the Void absorbs everything in the room without a need to choose one item.
  • Plan C seems to be something of a last resort item, as it deals 9,999,999 damage to every enemy in the room...but then kills Isaac three seconds later, meaning you'll lose if the exit doesn't spawn right where you're standing. However, if you have a character that can come back from the dead, like Lazarus, or have an item that can revive you, like Dead Cat, it's effectively a button to instantly deal with any boss you don't like. It is most useful during the fight with The Beast and the 4 horsemen, which if used immediately wins you the run without dying 3 seconds later. It'll even take out Delirium, but this only works for Lazarus or if you have Inner Child in Repentance.
  • The Smelter is similar to the Void, but works on trinkets instead, permanently adding their effects to you. This is broken for things like Cancer, the Hairpin, and so forth. Like the Void, prior to a nerf, it worked on single-use trinkets, most notably the Missing Poster, essentially making the Lost immortal since that trinket revives the player as the Lost.
    • There's also Smelter + Store Credit, which functions the same as having two Steam Sales, Smelter + Monkey's Paw, which works as a sin heart version of Scapular, and Smelter + Walnut, which drops consumables and a new trinket every time you take damage. Again, this got nullified by a nerf.
    • Combine it with Mom's Box using Void. Make Trinkets then absorb them over and over.
  • The D1, Isaac's Greedier Mode unlock, has the simple property of duplicating a random pickup in the room. In addition to all the normal pickups, this includes chests. However, if you remove all but one pickup from a room, then the D1 will duplicate it without fail. This essentially allows you to mimic the functions of the Blank Card and Placebo in a single item, albeit more tediously, or spawn as many chests as the floor will allow. Mix it with the Car Battery and a battery consumable to create infinite batteries and thus infinite charge for a floor, since it will create two batteries for every one consumed.
  • By completing Greedier Mode with Cain, you unlock Sack of Sacks, which has a chance to drop a sack every room. This is the Greed Mode version of Sack Head, as it will spit out sacks on a fairly reliable basis with every wave. This is a godsend in a mode where you have to pay for bombs and keys, plus it spawns all sorts of useful cards and runes. With Lilith, it gets absolutely ridiculous. Sack of Sacks is copied by Box of Friends. The sacks produce batteries to produce more familiars to produce more batteries each round until the arena is literally filled with drops. Some of those drops will probably be the 2 of Diamonds, so you have a lot of money, which means more items. Even though you can't abuse it with Ultra Greed, by the time you get there you shouldn't need to, even in Greedier Mode. It's not too shabby in the normal game, either, as it is essentially an independent Sack Head that spits out sacks without negating the room drops.
  • Little Horn grants a special piercing tear that can instantly kill any non-boss enemy. Cool, but not too overpowered unless you can beef your luck pretty high. However, the tear can also kill blue and purple fires, the invincible floating skulls, Stoneys, the eyeballs of Peep/Bloat, and Ultra Greedier during his transition phase from Ultra Greed.
    • Euthanasia goes even further: it grants special tears that can not only insta-kill enemies, but make them explode into a ten-way burst of tears, each of which deals triple damage. For extra fun, combine it with Cricket's Body, The Parasite, or Compound Fracture to have the instant-kill tears split into more instant-kill tears.
  • Butter Bean is normally a useless item that grants a three-second rechargable knockback fart that can also reflect enemy bullets. In Afterbirth+, however, it has a small chance to transform into Wait What? when picked up. Wait What? takes ten seconds to charge instead of three, but instead of farts it shoots out destructive rock waves. You no longer need bombs and it does decent damage to enemies. Furthermore, if you get Butter Bean, all you have to do is wait for another spacebar item and swap them endlessly until Butter Bean changes into Wait What?, making obtaining it a matter of persistence.
  • Libraries by themselves become an easy way to abuse the Book Worm transformation that needs you to pick up three books — Libraries usually have three books in stock on average, if not four, though you can get unlucky and only find two. Even if you don't need the books themselves, the transformation is a straight upgrade with no downside for the cost of a single key.
  • The I'm Drowsy pill induces a room-wide slowdown, as the counterpart/"good" version of I'm Excited!!!, just without the tricky time-delay (meaning it's good for only one room, instead of carrying on to others like its counterpart). However, this slowdown lasts for the entire room, including through all waves of Boss Rush, the entirety of the Hush fight, and Delirium. Like other enemy-slowing items, it slows bullets in addition to the enemies themselves. With the possible exception of Delirium, just about everything becomes a joke when slowed down. It's effectively pre-nerf Stopwatch in pill form, and when combined with Placebo, one can cruise through roughly every four rooms without much to worry about.
  • Tarot Cloth doubles the effect of your cards (with some exceptions). It's pretty good on its own when combined with things like The Hierophant, the Jera rune, and 2 of Diamonds, and absolutely bonkers with the Blank Card, letting you do things like pulling four Soul Hearts out of your ass every four rooms or flooding a room with pickups. To make it even crazier, throw in the Car Battery. How would you like eight Soul Hearts every four rooms, or maybe two whole minutes of invulnerability?
    • Then you add a Battery and do the same twice per room. And a Habit to retaliate with more when you're being hit by an enemy. ??? becomes literally unkillable.
  • Mr. ME! is a great asset in normal play, but utterly BREAKS Greed mode. You can use it to nab items in Shops or Devil Rooms without paying, and since Greed Mode lets you recharge items pretty quickly and has a shop that always restocks, you can gain a bunch of items for free.
  • Trisagion was an item added in the fourth Booster Pack that replaces your tears with beams of light which only deal a third of your damage, but are piercing and can hit the same enemy multiple times. While it can be weak on its own, it opens the door for all kinds of powerful combinations that can tear through the whole game. Most notably, if you can make your shots homing then they'll seek out enemies and stick to them, constantly draining their health away.
  • Pop! + any multi shot item (like Mutant Spider) + any splitting tears item (like The Parasite) = a minefield of eyeball tears that will hang in the air for quite a while, and violently blast away with splitting tears if they so much as brush against an enemy or impenetrable surface. Combine with a high fire rate and the screen can be easily covered in eyeball mines that leaves no safe spaces for enemies. Hell, it even makes a Scrappy Weapon like The Wiz viable, since firing two tears at once lets you cover the screen more effectively, compensating for the removal of forward firing. Continuum makes it better, with its main effect and the added range and tear height letting the eyeball mines stay for far longer. This combo works fantastically for Greed mode, where you can leave traps for enemies to spawn into and potentially immediately die or at least take serious damage.

    Repentance 
  • One item that amplifies the power of Brimstone is Eye of the Occult. It works like an inverse Anti-Gravity, in the sense that fired tears stop when you release the fire button. On its own, it's alright, but not terribly powerful... but then you get Brimstone, and suddenly you're firing lasers in any direction you please, with a handy cursor to see where you're actually firing them. This even works with Azazel's gimped version of Brimstone, so if you get really lucky, you turn a Crutch Character into a bonafide badass for endgame. The combo does have some issues to be aware of (namely that instead of a straight laser, it curves around to hit the marker then returns to you, leaving a fairly big gap that enemies can avoid it in), but it's still pretty damn powerful once mastered.
  • Book of Virtues is a big run-winner added in this DLC:
    • Bethany is a Magikarp Power character who really struggles in the early game, what with lacking any bombs/keys/coins and having to rely on her fragile Book of Virtues wisps to do meaningful damage without damage boosters, plus she can only gain eternal and regular hearts (soul and black hearts are instead used to charge the Book's extra uses). However, given the Book's nature as being able to stack with other active items, this means that if you get one-room-charge items, like say, Wait What?, Kidney Bean, or Tammy's Head, and suddenly you're able to frequently summon wisps every room or so. Combine with charge-producing items like Habit and the various battery-related passives, and you'll be easily popping out wisps like crazy. Especially if you have a way to mitigate the health loss that comes with using the Habit. And with the numerous effects that the wisps gain depending on the active item mixed with the Book of Virtues, you'll have lots of interesting combos to work with.
    • Book of Virtues + Potato Peeler = infinite wisp spawns. Here's how it works - Potato Peeler sacrifices red heart containers to summon a Cube of Meat per container and make a Meat Boy for every 4, but if there aren't any to spare, it does nothing, serving as an Anti-Frustration Feature so you don't accidentally kill yourself. But the Book of Virtues still registers it "activating" even if it doesn't do anything, so it spawns a wisp anyway. While normally you can have up to 8 wisps at a time, these wisps are special in that they float towards enemies that draw near and rapidly barrage the target with tears. You're free to spawn even more while they're away, adding to your army. Basically, you can pull wisps out of your ass whenever you want. The only major issue is the inability to hold onto red hearts for very long, but this can be remedied if you have the Wafer, Dark Bum, and/or other items that increase the chance for soul/black hearts to appear or mitigate damage. This is all on top of Potato Peeler's ability to put together Meat Boys.
      • This can get especially powerful if you play as Eve (who has Whore of Babylon and Dead Bird from the start) or Tainted Eve (can use up any health to spawn blood clot minions and add even more power). ???/Blue Baby/Tainted ???/Blue Baby (can never get any red hearts, only soul/black hearts) and The Lost/Tainted Lost (can't get any hearts period) can also make use of it to help bolster themselves if their damage is lackluster in later stages. Even without the Meat Boys, there's some major damage potential with this combo, and it works with pretty much any character.
    • Normally, Isaac's Tears is a poor item that only shoots a burst of regular tears once every 6 tears shot. However, when combined with the Book of Virtues, it enables a near constant creation of wisps that block shots and shreds enemies at an alarming rate. Sure, they only last 3 seconds, but because Isaac's Tears recharges so fast, that hardly matters, and because the wisps scale with Isaac's stats, picking up both items is almost certainly a run winner.
    • Shoop Da Whoop is normally a decent item, but it becomes one of the best in the game when combined with Book of Virtues. Each Shoop Da Whoop wisp creates a full-power laser alongside Isaac. A measly 2 room charge makes amassing a horde of these trivial if you’re even slightly competent at dodging. With enough wisps and damage ups, this combination is enough to shred late game superbosses such as Delirium in seconds.
    • The Eraser erases an enemy from the rest of the run, with the caveat that it can only be used once per floor. However, not only can Bethany and Tainted Bethany use their respective Soul Heart and Red Heart charges to throw more erasers at the cost of one heart per eraser as needed, they can use the Book of Virtues to throw an eraser and summon an Eraser Wisp which will also erase the enemy that extinguishes it. With enough heart charges, you can stroll through the now-completely-barren floors with this combination.
    • Unicorn Stump spent most of its existence as a middling item that was only really useful if you had an orbital or really needed to get into a curse room without taking damage (and was often outclassed in that department by other items anyway), but its Book of Virtues combination is among the best. The wisps it creates are near identical to those generated by My Little Unicorn—they're extra-durable and deal contact damage—but they can only be summoned in the middle ring and deal less damage to enemies. So what makes this a run-winner? Unicorn Stump has a charge time of one room. Coupled with the invincibility Unicorn Stump already gives you, this lets you plow through almost any room in seconds without taking a single hit. Even the final bosses get shredded.
  • Tainted Bethany: Instead of the Book of Virtues, she wields the Lemegeton, whose wisps instead summon a wisp depicting a random passive item. As long as that wisp is kept alive, you get to keep that item. And since the Book is charged by the much more plentiful red hearts, you'll soon amass a ton of items to steamroll the rest of the game.
  • The Red Key. Using it can create an entirely new room. This room can be anything from a regular enemy-filled room, to an item room (even on floors where they wouldn't normally spawn), to a Devil Deal, and so on. By creating enough rooms to leave an invisible 13 x 13 grid, the player can even create an I AM ERROR room, and skip to the next floor.
    • The real kicker comes in when you do this in The Void, which resets the floor, allowing the player to get more items and repeat the process, ad infinitum. If used in The Chest or the Dark Room, it teleports you to The Void, allowing you to fight Delirium.
    • The Red Key is also one of a few ways to find Ultra Secret Rooms, which have at least one Angel Room item costing a single key at most. With knowledge on how the Ultra Secret Room is placed and a bit of luck, every floor will grant one new angel item on top of what can already be found through devil deals or angel offerings, and any other special rooms spawned with the Red Key.

  • Revelation. Imagine you took a pre-nerf Brimstone, then add in flight plus soul hearts, and what do you get? Something that makes angel rooms a lot more appealing.
  • Tainted Cain is one of the most frustrating characters in the game but also one of, if not THE strongest character in the game. If he touches a pedestal item, it bursts into a bunch of consumables based on the item pool it's from. These can then be picked up by the Bag of Crafting, which can store 8 consumables, such as hearts, coins, keys and bombs. When the bag has 8 items you can hold down the activate button for 2 seconds to craft yourself a brand new item, including some of the game-breakers here.
    • In Greed Mode, you can use this to craft several Steam Sales, reducing the price of shop items to practically nothing. From there, simply collect items over and over, at a practical guarantee that the cash payback will excess the loss. You can create nearly any combo you desire to kill Ultra Greedier, then craft Schoolbag, R Key and Clicker using a resource like this chart or this calculator. You can easily kill Ultra Greedier again with another Tainted character. If you also craft Ankh/Judas' shadow/Lazarus' Rags and then use Clicker after dying, you can even do it with Normal Characters.
    • See here for more.
    • Tainted Cain has no limit on the number of copies of an item he can collect on a single run; if he has the pickups to craft it, he can have it. This means you can collect Eden's Blessing multiple times throughout the same run, then start your next run with an arsenal of free items out the gate.
    • Overall, once you get over the initial hurdle of not being able to collect items normally, Tainted Cain is extremely strong as he has significantly more control over the items he collects than any other character. If you can find the consumables necessary to make them, then you can have just about any game-breaking, once-in-a-blue-moon item or synergy listed on this page, just like that. That's not even getting into how he can craft items to generate more consumables, which he can then craft into even more powerful items.
  • Bomb Beggars now spawn multiple troll bombs when you attempt to bomb them. If you have the Safety Scissors trinket equipped, all the bombs are converted into bomb pickups, creating an infinite supply of bombs for the floor. Those bombs can be then fed back to the beggar for a plentiful supply of coins and hearts, eventually granting a bomb item.
  • Psy Fly is hands down one of the best fly orbitals in the game. It has the effect of intercepting shots that would hit Isaac and converting them into homing projectiles. It does the former at an astounding rate, such that even Bullet Hell bosses will have a hard time getting anywhere near you as long as you make an effort to stay away from heavy bullet spam.
  • Cursed Penny is a trinket that teleports you to a random room every time you pick up a coin. Downright useless for most characters, it becomes absurdly broken for the character who unlocks it; Tainted Keeper. Every time Tainted Keeper kills an enemy, they drop a coin. When you teleport out of a room, that room resets. If you're patient enough, it's a one-trinket infinite money combo. Since Tainted Keeper also gets enhanced shops with extra items, it lets him farm each floor with impunity.
  • The D Infinity went from an annoyingly inconsistent item to a fantastic one with this DLC. Instead of picking a random die, it effectively gives you all the dice items at once, able to cycle between them with the drop item button. On top of literally being the already bonkers D6 or D20, you can make utility plays like D12ing to get unreachable consumables, D4ing/D8ing if your run is going south, or min-maxing with the D1. The trade-off is that it now copies the charge time of the selected dice, and was moved from treasure rooms to secret rooms, but overall it's a run-winning item now.
  • Tainted Judas cannot have any regular hearts. Converter will try to give regular hearts but instead will just refund the black heart. When Converter consumes a black heart it deals 40 damage to all enemies and gives him another black heart, enabling an infinite loop that deals infinite mass damage to all enemies.
    • Tainted Bethany has a similar interaction, see [[here.
  • Dark Arts is an extraordinarily powerful item. To start with, it provides a one-second invulnerability period and speedup on an 8 second cooldown, which can be used to avoid difficult attack waves, skip puzzles, and open curse rooms with impunity. However, what it also does is mark enemies and projectiles, and once the invulnerability ends, you blitz through everything you touched, gaining increasing damage buffs for everything hit. With practice, you can exploit enemy attacks to become immensely powerful, to the point where bullet-spamming bosses like Hush and Mega Satan can be completely decimated if you take 20-30 shots in that brief period. In addition, the shadow strike scales off of damage, so if you manage to find Ipecac, your melee strikes can shred some bosses in a single hit if a few bullets are tagged first. It's very easy to practice with as well, as Tainted Judas starts with it in every run.
  • The Ghost Pepper gives you a chance to shoot blue flames, similarly to the Blue Candle active item, the chance of which scales with luck. On its own, it is nice but not too overpowered. However, there also exists a trinket called Perfection, which gives an insane amount of luck but requires the player to play a No-Damage Runnote . Playing as The Lost or the Tainted Lost? Enjoy your tear flamethrower that deals insane damage and also blocks shots.
  • The R Key is a very rare but VERY powerful one-time use item that resets your run with your stats and items intact. It can allow the player to clear multiple routes in one run, such as getting a good break in the Chest, rerolling secret room items to the R Key, then blowing up the more difficult alternate path with a full prior run's worth of equipment to trivialize Mother.
  • The Spindown Dice, which is unlocked by beating Delirium with Tainted Isaac, is amazing as well. It rerolls all pedestal items in the room into the item that has an internal ID one less than its own - assuming you have that item unlocked, of course. This may not seem powerful at first, but many common items can be rerolled into possible run-winners. For instance, the Blood Bag, found by donating to a Blood Donation Machine until it explodes, becomes Brimstone. Lazarus' Rags can be rerolled into Godhead. Bot Fly can be rerolled into freaking Death Certificate. Even outside of those specific instances, it's a min-maxxer's dream item, essentially functioning like a no RNG D6 that can theoretically reroll anything into exactly what you need.

  • Similar to The Lost, Jacob & Esau's unlocks are worth the pain and tradeoff:
    • Rock Bottom is a passive item that prevents your stats from going down for the rest of the run (it does not effect hidden stat multipliers, and it takes previous buffs applied into account to limit stacking). Its obvious applications are for items with huge stat tradeoffs like Polyphemus and Soy Milk, but with temporary stat changes taken into account it gets even more depth. Many active items and trinkets with temporary effects can be maxed out and discarded while keeping their stat benefits forever, especially by using recharges to use them a lot in one room. You can get benefits from items like Epiphany without having to confide by their restrictions, and consumables like Red Stew become permanent boons. It also nullifies most bad pills while still synergizing with False PHD, giving a constant stream of safe damage upgrades.
    • Magic Skin uses up a Heart Container to generate items. The heart is replaced by a broken heart that cannot be replaced by other pickups, essentially lowering your maximum health. Repentance nerfed it so that The Lost and Tainted Lost will be able to use the item once, after which it disappears. However Tainted Jacob in his Lost form can use the item up to 12 times, after which it disappears. He does not gain broken hearts.
    • Picking up The Stairway allows Isaac to visit a special Angel Shop at the start of every floor, selling Soul and Eternal Hearts, keys, and Holy Cards at 5 coins each, and more importantly, Angel Room items for 15. Considering that includes the likes of Sacred Heart and Godhead this is a big deal. The best part is that it really does appear on every floor, meaning it not only shows up on the floors after the Womb where regular Angel and Devil Rooms no longer spawn, but if you pick up Dad's Note, it'll be at the end of every single mini-floor you visit on your way back home.
    • Genesis: upon use, your character, including stats and initial items, is reset and teleported to a unique Bedroom that acts like an I AM ERROR room. It has a Bed, two random Chests, two Sacks, and a random Trinket. The only way out is through the beam of light. For every item removed using Genesis, there will be a set of three items from the removed item's pool to choose from, each set appearing one after the other. If you save and quit, there will be more items for you to choose from, eventually making this turning into Death Certificate-lite.
    • Play as Tainted Samson, collect Berserker! and the Schoolbag, or Use a Soul of Samson, and collect Suplex. Now, grab anything enemy or bosses whatsoever while you're berserk. And watch them as they are instantly deleted after your berserk state expires. It can work on absolutely anything: from a Black Fly to The Beast. Just be careful to not use it against Dogma, as you'll be trapped in the boss room if it's deleted.
    • Damocles: Upon use, summons a sword that hangs directly above Isaac. As long as the sword hangs above Isaac, all item pedestals and items spawned from Machines and Beggars are doubled, spawning an additional, free item next to them. After Isaac gets hit once with the item activated, at any time without warning, the sword may fall, instantly killing Isaac regardless of his health. If used with Magic Skin or Genesis, it eventually spawns more items.

  • Echo Chamber makes it so that when using a pill or card, it activates every single effect of all of the pills and cards used since obtaining Echo Chamber. Combining this with Ancient Recall (spawns 3 random cards) makes it so that you can draw and use as many cards as you want! (You can alternatively use Vurp! for infinite pills) See here for more details.

  • Tainted Eve can rip apart everything in her path once she has something like Brimstone or Ipecac. Her blood clots copy her tear effects, and this includes the lasers and explosive shots. With enough blood clots assembled, you can effectively delete everything in your way as soon as you enter the room. It does come with the typical downsides (long charge time for Brimstone, self-inflicted explosion damage for Ipecac), but items that fix those (tears ups, Host Hat/Pyromaniac) will make it much safer and easier to use.
  • Deep Pockets received a rework in Repentance. It now boosts your coin cap to 999, and gives you one to three coins whenever you complete a room that wouldn't have given a reward otherwise. On its own, it's a nice enough item, but once you add Money = Power to the mix, things quickly get out of hand. Your wallet size increasing tenfold means the potential damage boost from Money = Power has also increased tenfold, and even if you're unlikely to fill it up completely on a normal run, the extra coin drops all but ensure you'll have enough to deal ridiculous amounts of damage by the endgame.
  • Aries was a sub-par item in Rebirth and Afterbirth, but got a huge buff in Repentance. Initially, it did contact damage when moving fast enough and came with a speed buff, but came with the obvious drawback that contact damage would hurt you at the same time. Repentance buffed both the damage and made it so you are immune to contact damage as long as you're able to deal damage with it. Contrary to the item's name, ramming isn't technically required; you just have to make contact. With a little practice, you can sideswipe most enemies and even some bosses with no risk of harm, dipping in and out to avoid bullets.
  • Similar to Tainted Judas, there is another infinite loop involving Tainted Magdalene. Since Sharp Plug takes two hearts to charge and Yum Heart grants 2 full red hearts when used, it can be used infinitely without losing HP. Doing this will also prevent HP to decay while doing this infinite combo. Additionally, the Invincibility-frames from the damage taken last long enough to become permanently immune to any other damage source. Tears can't be fired while doing this, but it is still possible to kill enemies with Tainted Magdalene's melee ability, basically guaranteeing a win on the spot. Binding the "use pill" key to a more accessible key to move around easier is recommended.
  • "The Emperor?" card teleports Isaac into an extra Boss Room from the boss pool two floors deeper than the current floor. The boss will drop a reward, but doesn't spawn a trapdoor and instead drops you back into the room you used the card in once you use the exit door. However, if used on the Hush floor, it teleports you to a Monstro fight. Defeating Monstro counts as defeating Hush, allowing easier access to Delirium. See here.
  • Mega Mush, unlocked by earning all Hard mode completion marks for all non-tainted characters, turns Isaac into a giant for 30 seconds, an effect that persists between rooms. This makes Isaac invulnerable to damage, provides him with quadruple tear damage (but with a much greater tear delay), the ability to destroy all objects he walks over — even the otherwise invulnerable metal blocks — bash through doors without having to clear a room, and extremely potent contact damage to enemies. It's basically an off-button to any fight you don't like, hampered only by its 12-room charge. Using it while it is already active increases the duration Isaac stays giant, and Car Battery doubles the time per use, so with enough charge-related items and trinkets it is possible to stay giant for the entire floor without having to worry about any periods of down time.
  • And finally, Death Certificate, unlocked by getting all hard mode marks with all 34 characters, teleports you to a special floor containing every item in the game, separated into a couple dozen different rooms. Even items you haven't unlocked are available. You can pick a single item, then are teleported back to your original location. This is decent as is, but with certain items leads to a lot of exploits.
    • If you have a way to carry two active items (either by finding the Backpack or by playing as Jacob & Esau) and the Void, you can use the latter to absorb a ton of items at once, resulting in a significant power boost. Even better, you can still pick one more item.
    • Likewise, Moving Box allows you to steal six different items.
    • A major (and likely to be patched) exploit can be performed with the Forgotten and Birthright. Birthright, when used by the Forgotten, unchains the Soul from the Forgotten. The Soul can move through rooms freely, leaving the Forgotten in the room you first switched. If you switch back, you are teleported to the Forgotten's location, even out of a hostile room. The exploit comes when you combine this with the Death Certificate animation. First, leave the Forgotten in the starting room and use the Soul to pick up an item. When an item is picked up, a death animation precedes the teleport. By swapping back to the Forgotten during the period between the death animation and the teleport, the teleport is canceled out. You can then repeat the process in another item room, since the game only destroys the items in that specific room after one is picked up. With careful timing, you can collect 20+ items, one from each room on the Death Certificate floor. Just make sure not to do so on the last item, or you'll be trapped. Check it out here.


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