These are what we call the 'YMMV items.' Things that some people find in this work. We call them 'your mileage might vary' because not everyone sees these things in the same way. This starts discussions in the trope lists, a thing we don't want. Please use the discussion page if you'd like to discuss any of these items.
Are the other playable characters alternate personalities? If not, are they related to Isaac? Is ??? one of them?
Is Mom a religious zealot, just insane, or both? Did she go insane from religion, raising Isaac, or her husband leaving them?
Is God evil or good in this game? Did He have Mom sacrifice Isaac for fun, as a test, or because he was the Anti Christ? Did He even ask her to do it or was she just imagining things?
Is Satan trying to protect Isaac or awaken him as the Anti Christ? Does he just see Isaac as a customer and tries to get more payment in the Sheol path?
Did Isaac's Dad leave because he was a Jerkass, didn't feel like he could be a good family man, or to get away from his mentally unstable wife?
Anti-Climax Boss: War's first phase is exactly what you would expect having seen Pestilence and Famine, with no summons but more aggressive attacks. His second form... is basically a quicker Lust but saddled with Gemini's poor running stamina, far too late in the game to be very intimidating for anyone with speed upgrades.
Mom's Heart/It Lives will rarely pose a serious threat to anyone who is good enough to reach it.
The red champion version of Mom looks impressive, but is actually far easier to beat due to her greater attack speed and lack of Mook Maker abilities. Players can just dodge the telegraphed foot attack and retaliate, occasionally dodging a bullet spread from her eye.
He's pretty well-known for his awesome video-game music (as can be heard in Canabalt and Super Meat Boy).
Special mention goes to the battle themes: "Divine Combat", "Burning Ambush", "Thine Wrath...", "...Be Done", and "Enmity of the Dark Lord".
And Wrath of the Lamb adds "Unholy Assault", "Crusade", and the absolutely majestic "My Innermost Apocalypse".
Edmund has started teasing the brand spanking new music for Rebirth, which comes with the sad revelation that Danny B. is not returning, but Matthias Bossi replaces him. The three revealed so far, Dipterra Sonata for the basement, Ventricide for Mom's Heart/It Lives and Duress for Sheol all bring on a new, more disturbing vibe.
Best Boss Ever: Loki, an always-smiling demonic baby, is quite preferred over Monstro II as the boss of the fifth floor. They even call him "Mr. Cool" in the credits.
Satan, boss of Sheol, is the most complex boss fight in the game and is the only boss to have multiple complete health bars. Before he even lets you fight him, he sends out one of The Fallen at you, and once you beat him, he breaks out of the statue and goes berserk, using updated versions of The Fallen's attacks. And after you beat him... he gets right back up, flies offscreen, and uses Mom's battle strategy as the fight becomes more fast-paced with him constantly stomping on the floor. After you beat him here, he finally falls and gives you Ending 11.
The bosses which spawn in the Brutal Bonus Level are noticeably less difficult than earlier bosses. Harbingers also tend to be nerfed to second stage only. Not so, however, in the TRUE Brutal Bonus Level, which can quite frequently feature any Harbinger (even Death is normally fought only two levels ago) in a room far more restrictive than the one you normally fight them in. They're not nerfed, either; they're exactly the same as the actual boss fight.
Pride's diagonal tentacle/shout attack probably won't hit you if you're firing at him with your tears, and his bombs are for the most part easy to avoid.
Lust is a Bullfight Boss set up in an arena with rocks to slow her charges. Unless your character is very slow, she's incredibly easy to beat even in the opening level. Her upgraded version leaves a damaging trail of blood, but it tends to fade by the time you circle around.
What about Wrath and his penchant for blowing himself up? He's not very quick-moving and his only means of attack can be used against him easily. His bigger version, Super Wrath, however, is a nightmare. His bombs follow you around the room, even flying over the rocks in the way. Unless you've been lucky enough to get an invincibility item or have maxed out your speed, you're going to take some damage.
Scolex was formerly this. It's only fought in Womb I, but due to its very low health pool, it's fairly easy to defeat. It was buffed in Wrath of the Lamb, but it's still easier than other Womb I bosses like Lokii (the second version of Loki in which Loki is split in half) and Death.
Gemini and its variant Steven are, even in spite of the others having additional tricks, incredibly easy to beat. As long as your character isn't lacking in speed, they can't catch you and their bullets usually won't hit you. (Ironically, Blighted Ovum, the third variant, is one of the hardest bosses in the game).
Pin the worm is borderline impossible to get hit by once you've locked down his pattern. Hanging out on the bottom of the screen causes his bullets to miss every time if you aren't in the path of the head.
The green champion version of Gurdy, while still high on health, doesn't shoot bullets, instead preferring to spawn flies. This makes it easier to avoid her attacks.
Gish is essential a retrained Monstro that fires a single slow-moving explosive and spawns enemies that only fire diagonally. Players skilled enough to unlock him will most likely never take a hit to him, and he drops Little Gish, a familiar that shoots useful slowing tears.
Breather Level: Even during the Brutal Bonus Level, there will occasionally be rooms with only a fly or a pair of helpless grubs, which still recharge your special item and have a chance to drop items. There will also always be some empty rooms, and it's possible to spend quite a long time in the arcade with virtually no chance of death.
Broken Base: Rebirth caused one initially from fans who didn't like the idea of rereleasing the game instead of getting more content and drastically changing the art style, but this one died off pretty quickly when Edmond mentioned that because Bo I was made in flash the game simply couldn't handle more content being added while still functioning. The trailers and screenshots that have shown the new synergy between items that formerly had none (like Loki's horns+ Mom's Knife) has silenced the detractors even further.
Leapers, the bane of any player going for a No Damage Run. Their erratic jumping makes them hard to hit consistently, they can jump to any part of the screen with little warning, and when there's four of them, the screen tends to be filled with bullet spam from repeated jumps. A real pain to deal with.
Mr. Maws. They swing their head at the player, which can be very hard to dodge, and upon death, they leave shooting heads (and sometimes slow-moving bodies) behind which can be a problem of their own. Even bombs and Brimstone (unless buffed with extreme damage) won't get the head on the first hit. They can be the utter bane of people going for No-Hit runs, because there's one room configuration that they are practically impossible to dodge as you enter.
Psychic Maws. They're a variant of Maws, which are already annoying enemies. These fire homing tears, have increased health, and have an Eternal Fly circling around them which can block hits. Fortunately, they are rather rare.
Knights have a rock-solid front end that shrugs off almost all attacks. Its weak point is the exposed brain on its back, but good luck getting a clear shot at it, since they have a tendency to turn around and run right into you after you position yourself behind it. To make matters worse, there's a version of this enemy with Isaac's face in place of the brain which charges at you at full speed.
Eyes, especially when they're not located in the center. These are likely to hit the player. The bloodstream versions are even more dangerous (especially without having a weapon to shoot over rocks), as bloodstreams last longer than Eye Beams and they're often situated between rocks, making it hard to hit them.
Clotties, when in groups or in certain room layouts. They move around haphazardly, fire in all four cardinal directions at once (which forces you to either put yourself in danger to hit them every time or use unreliable diagonal shooting, which may not always be viable in certain layouts), and do so at completely random intervals (i.e. not guaranteeing you'll even have enough time to try to hit them) with next to no warning. Even worse are I.Blobs, the white "Alternate" varieties that do 8-way shots, making even diagonal shooting dangerous. Fortunately these are extremely rare, but if you are unlucky enough to see one in a floor, expect to take some damage.
Wrath of the Lamb has the jumping spiders known as Trites. They're just like hoppers, except they move at nearly double speed, take more hits, and often come in packs of 4 or more.
Chubbers. They have the same appearance as a Vis (the walking stomachs that shoot giant lasers at you) but have a small Chub housed inside each of their bodies, which fires rapidly, can go through rocks and walls, and takes out a whole heart of health. It doesn't help that they have an insane amount of HP and often come in packs of 5 or 6.
Keepers. They're the little bouncing Greed heads. They jump around erratically like leapers, put you through bullet hell, and every single shot or collision with them makes you drop coins, making one lost forever. Much like spiders, they have the uncanny ability to squeeze between boulders and pits joined by one corner. They often come in packs of four, and Super Greed is all about spawning these.
Hangers, which are basically hostile shopkeepers. They fire three way shots, have Eternal Flies circling them, and have a ton of health.
Masks and Hearts. The mask is invincible, and is connected to a heart which can soak a lot of damage. The masks charge and have very good reflexes. The hearts try to flee from Isaac and if he gets too close fires four shots in the cardinal directions (like the Clotties) to defend itself. Fighting them in rooms with rocks makes them even harder to deal with. Finally, they are rarely alone. Good luck dodging the extremely nimble masks while trying to get a clear shot at the hearts, which retaliate on their own accord.
And, well, basically every enemy in the Womb and Beyond, since they do one heart per hit instead of half.
Genius Bonus: When under the effects of Whore of Babylon, your character leaves a small puddle of blood rather than the usual puddle of pee left at low health every time you enter a room. This may be a reference to past conceptions of what periods were (a curse due to Eve's actions of original sin) or even to the Biblical passage introducing the Whore of Babylon, "...and I saw a woman sit upon a scarlet coloured beast..."
Knights are hard to hit since they're invulnerable in the front.
Hosts take cover and shoot 3-way shots. Sometimes weird maneuvers must be taken for them to show up. There is a red host variation which cannot take cover, but it shoots a 5-way spreadshot and fires more often.
The many varieties of flies fit the trope better. Especially the ones that shoot at you, or explode in a flurry of bullets upon death.
Similar to the flies, the many variants of spiders fit this as well. Not that hard to kill (once you learn the basics of dodging), but they are on every floor, many bosses and some mooks spawn them and they are JUST random enough in movement to chip damage you to death over the course of a long run. Good luck trying to kill them with the Ipecac or Fetus in a Jar.
Just mention Greed to anyone who's played this a few times and watch their blood boil. It's not just the fact that he's very hard to fight without being hit once (his attacks are completely random and have no tell whatsoever), but his appearance results in you losing the shop or secret room of that level. This can be annoying at best (meaning you've lost a key or bomb to get in for nothing), or utterly fatal (You SO needed that shop for health...). The exception is when not having enough money, as Greed drops a lot of coins.
Of course, if you have the D6 and are good at dodging, getting Greed in a secret room with the ability to enter over and over can lead to Greed farming. Add in the Habit and you have yourself a recipe to get every item in the secret room pool from one boss! That being said... Goddamned Greed!
The green variation of The Duke of Flies when not having any bombs or piercing shots. The Duke spawns Moters which can be dangerous if shot, and it's hard to get a hit on him. For that matter, any variation of the Duke of Flies can be this. He's one of the easiest bosses to beat with powerups. Unfortunately, he's always going to be either the first or second boss in the game when he appears. In fact, when you later see him as a Degraded Boss in the Womb or Sheol, it often turns into a Curb-Stomp Battle in your favor.
Monstro and Monstro II, for some. While their attacks are moderately dangerous (comparatively to the rest of bosses), they have easily the most health out of all the bosses for their respective levels, making the fight boring and thus, prone to mistakes.
The Krampus. Just by appearing he will invalidate any Devil Room you might have earned on the level. He also loves to appear early and takes forever to kill. His double burst fire attack is very difficult to avoid, even if you are running circles around him, and his cross blood attack has an incredibly short tell. Furthermore, the coal item he drops is of questionable value.
If you have the D6, the coal item can be rerolled for a random Devil Room item that you can then pick up for free, making the fight much more worthwhile.
The Mask of Infamy, if you lack a piercing attack (which you usually do). In her second form, she's pretty much a knight with near-perfect AI, meaning she'll chase you around the arena in circles and occasionally one or two tears will land on her backside by luck and actually damage her. You could probably try using a bomb or two, yeah, but she's constantly moving and you can't just plop one directly in front of her. By design or by bug, she is also the only boss lacking a health bar, which makes the fight much more infuriating.
The Bloat. He's a harder version of Peep and starts with both of his eyes out of his sockets. What's more is that if you stand right in front or to the sides of him, he will fire blood beams with next to no indication of doing so. This can happen as soon as you enter the room, so unless you have high speed and godlike reflexes, you WILL get hit.
Fortunately, the Bloat does not use the blood beam attack when attacking him from behind.
Mom can be this, especially to less experienced players. Dealing with the many mooks she can summon while dodging her stomps at the same time can prove to be a very difficult task. It gets worse when she summons Clotties, Maws and other projectile-using mooks. It doesn't help that rocks block the corners of the room and the doors have a chance of summoning her very fast and hard to dodge hand, leaving you with very little room to deal with your assailants.
After the Halloween Update, the Mr. Boom item's recharge bar got permanently stuck on full charge. That equals to an infinite supply of super-bombs! This one was fixed in the bugfix that quickly followed the Halloween update.
There was a bug where ??? gained complete invincibility when he took a Full Health Pill. This invincibility would last until he picked up an item that would increase the maximum health of a normal character. It even counted for No Damage achievements. Eventually, it was patched out.
As explained above, the Brimstone + Chocolate Milk combo was originally this, allowing you to spam blood beams all across the room for no charge delay whatsoever. However, this was quickly fixed for being too overpowered, and the resulting combo produced from it is now... less than satisfactory.
A bug that is not patched out, though, is the infamous Brimsnap glitch (named after the Lets Playerbisnap)): if you keeping tapping the button while firing the Brimstone beam, it will potentially double its damage and increase its area of effect.
Defeating the Headless Horseman will sometimes unlock Little Chad and the connected achievement, even if you haven't cleared the Caves enough times to even unlock Chad himself.
On the less spectacular but more exploitable end of the scale, if you use the Temperance card to create a blood donation machine right next to one that was already there, you can use the mercy invincibility from touching one to activate the other without taking damage, doubling the rate of payout per heart. This could be extended even further if you find multiple Temperance cards on one level.
Wrath's bombs are treated as player bombs in order to make them pushable. This means that certain powerups which alter player bombs also affect his. Such as the Bobby Bomb powerup, which makes your bombs move towards the nearest enemy. The result is a hilarious easy win.
Before it was patched, when using Lemon Mishap after defeating a boss and leaving the room through the door, re-entering the room would allow you to fight him again, earning you an extra item.
A similar glitch that is currently not patched is that using a Portable Slot in a boss room after the boss is defeated, and getting a fly to buzz around the room. If you leave without killing it, the room will reset, allowing you to fight the boss again and get its item. This also works for other rooms such as secret rooms.
Before it was patched, the final boss fight against Isaac himself bugged out and had no music at all. This made it way more dramatic than the standard "Dark World Boss" theme.
Wrath of the Lamb had, and may still have, a glitch where secret items don't need to be unlocked to be found.
It was possible to enter and exit Challenge Rooms at any time as long as your character could fly. In addition to allowing a player to enter Challenge Rooms without full health, it also allowed players to pick up the item in the room and then leave without fighting any enemies. This glitch was around since the game came out, to the point where it may have become an Ascended Glitch. However, the expansion Wrath of the Lamb made the glitch even more game breaking by including more items that gave flight, as well as advanced Challenge Rooms that always gave a major item. The second update to Wrath of the Lamb removed this bug entirely.
Wrath of the Lamb made it though that Curse Rooms only damage your character as he left them (usually damage is received when entering AND when leaving the room).
If you enter a room with 3 charge points or more The Battery in V1.5 (the store retail version with Wrath of the Lamb included) will give you #6 a lot sooner than usual, and reset the counter allowing a further three charges, enabling item use in every room, if you have the patience.
Charge #3 seems to happen without the charge icon appearing, and it doesn't affect the count.
Also in V1.5, The Habit randomly gives extended Mercy Time, mostly from enemy shots or contact hits. It doesn't tend to happen with explosive damage.
The Luck stat is not calculated correctly, resulting in Luck Down pills resulting in better drops.
And the classic of game-breaking circles: Abusing Scapular, the Habit and the D6 or the D20 for infinite rerolls.
Libraries and Devil Beggars can have their drops manipulated so that they pull from the regular item pool instead of books (in the case of the Library) or God/Devil room items (in case of the Devil Beggar).
More fun item pool abuse: with the D6 as the spacebar item, find Greed. Wait until he spawns minions, then kill him (and only him) and reroll the Steam Sale if that drops; if not, leave the room, come back and kill Greed again in the same manner (since the room doesn't count as having been cleared, he respawns). Repeat until bored, out of re-rolls, or you break the drop system by spawning an Undefined item.
Scrappy Mechanic: The Sacrifice rooms, where you give up health to get some random chest, are almost entirely useless and feel like a leftover.
Needing the Polaroid to enter the Chest, combined with the fact that Mom always drops it after it's unlocked unless you have v 1.5. Trinkets become less useful as a result since you can only carry other trinkets through the end of The Depths without Mom's Purse. Luckily, most cheat engines have an option to disable this, and Edmund has announced that Rebirth will get rid of the mechanic.
Scrappy Weapon: A few. My Reflection is a particularly infamous one, as it just makes your tears boomerang around wildly, cutting your range and making it hard to aim.
The king is the Dark Boy (Depths) No Damage Run. That level set has just the right combination of pits, Demonic Spiders, Goddamned Bats, indestructible moving spike blocks, and cheap-as-hell bosses (plus Mom) to make it an absolute nightmare to get through, no matter how absurdly overpowered your character is. Even the Womb is easier because it does not have pits.
Gurdy, a Damage-Sponge Boss early on, can't move but takes up half the room. She can fire five bullets in a spread pattern and summons sacs that fire more bullets, as well as flies. Compared to the other bosses, she's a real pain. It's easy enough if you get her pattern down, but the fight takes a long time. You also better hope you've upgraded your damage or tears, because the bullet sacs regenerate a lot faster than spider sacs do. A lot easier if you learn to exploit the space behind her where flies spawn, even easier if she spawns an explosive Boil, which tends to hurt her more than you.
The Widow from WOTL, a first-floor boss that jumps around like crazy, spits demonic spiders (the tiny kind), AND spawns sacs that in turn spawn more demonic spiders. Then there's a variation of this which spawns even MORE spiders, double spiders, and hopper spiders. She was thankfully toned down after release, but she's still a lot tougher than most bosses on that floor.
The Mask of Infamy, a giant copy of the mask-heart enemies. Don't let that description fool you. Its AI is a lot better than the mooks it takes from, and both the mask and heart need to be killed. The mask can only be hit from behind, and has near-perfect turning reflexes. If you don't have a piercing attack, expect to spend a long time fighting.
Super Wrath. He fires the homing troll bombs that pass through walls, and is tougher to kill. If you can't fly, it sucks to be you.
The Bloat. A ruthless version of Peep that invariably fires Brimstone the same second you enter the room, and also if you so much as graze the area directly to the sides or in front of him. Unless you've got very high speed, this will hit you. The only safe place you can attack from is behind him, and his eyes always seem to be behind him. Oh, and the eyes detach at start, not after taking enough damage like Peep does. A champion version will also send out a spray of Ipecac bombs towards you whenever he jumps, and can spawn Chargers. It is also possible to fight him in both Necropolis and Utero on the same run.
If you get to The Chest, always have more than one heart in case he turns up unannounced.
Gurdy Jr. Not so hard right? Then she charges at you and is almost always pin point accurate. And if she misses, she might just do a little homing slide into you. The variations and double boss versions only make her that much harder to defeat. Plus, like "her mother" Gurdy is one tanky boss.
Several of the Harbingers and Horsemen qualify.
The Headless Horseman is a Dual Boss. The body shoots bombs constantly, while the head shoots bullets with almost no warning and charges frequently. The charges will cover top, middle, and bottom, and not always in the same order. The head also appears as a Degraded Boss, sometimes more than one at a time.
Conquest, the new horseman in Wrath of the Lamb, has a charge which covers almost the entire screen, which can be impossible to dodge if you're too slow or get trapped too far from the safe area. There's little warning for his fast moving homing shots, and the beams he releases from the sky are impossible to dodge by your own ability (unless you have flight), you just have to hope they don't hit you. His AI sometimes has a small pathfinding bug where he slowly drifts into a corner and into the wall where normal tears can't hit, while he can simply teleport of screen to do more damage to you. Combine that with his whole heart damage for everything he does and Conquest can end your game. Conquest's gameplan is mostly teleporting so rush attacks (Game Kid, Unicorn, The Chariot) are much less useful than with most bosses. To make it worse, while Conquest can usually only replace Death, due to a glitch, he can also randomly replace War, who is fought two floors earlier.
Death, the final Horseman, is able to summon Scythes that home in on you. It's limited homing, but they are huge and hard to dodge. After you've damaged him enough, his mount detaches with its own (invisible) health and charges endlessly, even after you've killed him. On top of that, he spawns Knights.
Pestilence, is mostly a pain because of room design more than anything else. Fortunately his ipecac blasts will clear the rocks out eventually, unfortunately he is spawning grubs all over, and sometimes rapid fires his ipecac blasts which also cover the floor in toxic do-not-touch spots. Once you get to his second stage it is easy... good luck getting to his second stage one more than a heart or two.
And if you are unlucky enough to get a Pestilence and Headless Horseman combo in the Chest, here is hoping you got a lot of good upgrades on the way.
Ultra Pride is a Dual Boss. The main boss (Edmund) always does one full heart of damage without the Wafer and has an attack where he spontaneously creates a giant poison stream in front of him with long range. Then there's the familiar (Florian), who behaves like the Babies, meaning that he can teleport. In addition, he fires fast moving, long-range homing tears; the exact same type fired by Isaac and ???. Also unfortunate is that, if you're going for Platinum God, you must defeat Ultra Pride at least once.
The Blighted Ovum. Similar to Gemini, this one has the added "benefit" of being the same speed as the player sans-powerups and leaving behind lethal blood trails that deal A FULL HEART OF HEALTH IN DAMAGE, along with a "little brother" that pukes blood lasers.