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? What is His relation to the Angels?
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? How is he related to Mega Satan?
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. It is considerably more of a challenge in Rebirth, however.
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. With the game's release, we can safely say that the other battle themes are awesome, too, from a new version of Crusade as the normal boss theme, Matricide for Mom, the aforementioned Ventricide for Mom's Heart/It Lives, Hericide for Satan and True Final Boss Mega Satan, Infanticide for Isaac, Ascension for ???, and The Fallen Angel for newcomer The Lamb.
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 original 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.
Rebirth naturally tops Satan with Mega Satan, who combines Giant Hands of Doom, mixes in minor elements of Bullet Hell, and summons at least thirteen Degraded Bosses with a grand total of eleven phases. And then he still has one more form left, where he goes all out with the Bullet Hell in a last ditch effort to kill you.
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. In Wrath of the Lamb, Pin can be wiped out with one Bomb, absolutely fries to piercing attacks, and can bomb itself with his own ipecac shots. Rebirth fixes these weaknesses, making Pin not a total pushover, but the original strategy is still viable.
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 essentially 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.
From Rebirth is Mr. Fred. This is a boss that is fought in the Womb, but is completely immobile, is assisted by fairly non-threatening mooks, and his 4-way blood creep bullets can be nullified by flying or shielded tears. Depending on the room layout and player upgrades, it may be possible to kill the boss from a position where none of his bullets will even reach Isaac.
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.
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 BoI 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.
The super secret in Rebirth, The Lost, a Hidden Character. Hoo boy. What happened is that the game's creator put in a riddle that he anticipated would take months or even years for the whole community to solve. It was actually cracked in the week following the game's release, with the aid of people extracting data from the game's files and executablenote There was a text file in the game's folder explicitly asking people not to spoil anything they may dig out to others. This prompted the creator to angrily admonish the fans for ruining the riddle and announce that in future expansions to Rebirth there will be no more such secrets. There are many ways people are split over this:
Was the creator's reaction justified? He and the developers put lots of effort to ensure that the riddle would not be solved accidentally, but still accessible with the hints delivered in-game, and would be a fun experience for people to solve together. People then circumvented all that and just read the solution from the files. Or perhaps the backlash was childish, punishing the whole community for the deeds of a single data miner (with whom most of the fans were angry as well). Besides, the creator has grossly overestimated the time it would take for a huge fanbase to solve the riddle together, despite this happening time and time again in Alternate Reality Games.
How much the spoilers extracted from files actually helped solve the riddle. The general consensus seems to be that the riddle was already about 80% solved and would have been solved anyway in a couple of days at most, since the community had all the pieces and just needed to put them together. But there are claims that people only started getting hints after the first detail (that the solution has something to do with dying in a certain way) was discovered by looking at the game files. And regardless of that, some people say that the community circumvented most of the riddle anyway, since they were using cheats to immediately test out various circumstances instead of waiting for them to happen naturally in the game as was intended.
It's highly controversial that the creator, despite wanting it to be an elusive secret, made unlocking it into an achievement. A secret achievement, but there are legitimate ways of looking at those on pretty much all of the game's distribution platforms. And not only that, but there are other achievements, and even in-game items, that require unlocking the super secret. At this point, people who were not interested in the riddle but just wanted to have 100% completion decided that anything goes, which might have prompted the data mining.
Some say that it's a good thing that the creator will not be putting any more secrets like this into his games, because it was a poorly designed mess. It required way too much effort to be solved by any one person, so people not interested in the community (and this is primarily a single player game) or just left out of the loop at the exact time where fandom was working on the riddle would have no way of unlocking the secret (and any further items) other than just looking up the answer online. And there's the fact that while putting together clues may be fun, the unlocking itself requires a lot of time even if one knows all the steps and is a painfully boring, RNG-dependent grind that requires dying to certain enemies with certain characters in certain order (and dying in any but the right way will reset the sequence), which is completely unnatural and simply not a fun way to play the game.
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. Made even worse in Rebirth: their Chub now blocks tears!
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.
The new wall-crawling spiders in Rebirth. They come in three flavours: three-shot burst, triple shot, and Brimstone. The three-shot burst version is annoying but easy enough to kill. The triple shot one is blind, fires without warning, and moves random. Rooms can potentially have three of them stacked on one side, making it difficult to kill them without taking damage. Rooms with the Brimstone variety often have you taking damage immediately as you enter the room, sometimes twice from the same Brimstone laser.
The Walking Hosts. These enemies are much harder to coax out of their shell while they slowly walk to you, and often come in rooms where it's tricky to maneuver around. The 2x2 room containing four of these enemies and the perma-firing Grimaces is one of the most notorious rooms in the Caves.
Ensemble Darkhorse: The Dark Bum from Rebirth quickly became one of the most wanted items. When it was severely nerfed there was fan outcry for him.
Fandom Berserk Button: Using the Flash Filter in Rebirth will often get people to mock you for it, particularly those who use 4chan. This is most likely because of how blurry the filter looks compared to the non-filtered game, and the fact that Edmund only added the filter in as a joke.
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 and their many variants are hard to hit since they're invulnerable in the front and have unpredictable movement patterns. Some even turn to charge you. Past a certain point, piercing is practically required to survive. It certainly doesn't help that there's a boss version.
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.
Lil Haunt, the mook version of The Haunt, is an extremely cheap enemy. Their movement pattern is designed to lead you, which makes it very easy for them to corner you (but also extremely easy to control them if you know this). They have a bullet attack which has no tell or consistency. They are tougher than most mooks their size. Finally, they make the boss fight against The Haunt that much more annoying.
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. And then, when you DO need coins, the game spawns a shop instead.
And just because the developers love to see us cry, they've given us a hardmode version of him, with much wider bulletspray (though it also means he can't hit you from the front), more health, and he spawns Greed heads.
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 other infamously annoying Sin is Envy. While he has the same chance of spawning as the Sins other than Greed/Super Greed, Envy is just flat out annoying without a powerful build. He's a particularly irritating variant of the Asteroids Monster who splits numerous times, and all he does is fly around diagonally. While not particularly tough, the fight takes forever, to the point where many have actually given up runs if Envy spawns early enough and Isaac doesn't have any items to make the fight go faster.
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, which makes trying to shoot through his fly mooks extremely annoying. 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. They can also render themselves immune to most attacks just by jumping (which they'll be doing constantly,) making it hard to hit them with bombs or certain pick-ups.
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, as it requires Brimstone or high range to be truly effective.
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.
In Rebirth, he drops the much more useful Head of Krampus, an item that unleashes a very powerful four way brimstone shot that can clear rooms easily and do serious damage to bosses. It ended up being so powerful that version 1.031 nerfed it from a three room charge to a six room charge.
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 (but not in Rebirth), 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. If you enter from any direction other than the top, this can happen as soon as you enter the room, so unless you have high speed and godlike reflexes, you WILL get hit. The only mercy is that his bloodbeams can't shoot up, but then he may just leap to the top of the room and crowd you out.
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. She's even worse in Rebirth, since the stomps come out faster and the shadows warning of them are much harder to see.
Rebirth brings out The Haunt, a ghostly spectre and his three familiars. As mentioned below, the familiars are very hard to fight without getting hit, he's a Cellar boss, and he has one of the highest HP totals for that point in the game, meaning you likely won't have enough power to give him a fair fight. Plus the fact that you can fight two of him at once in some rooms. Feel free to keep your hand hovering over the "R" key before entering the boss room...
Rebirth also adds Dingle, a living poop monster which is Gurdy Jr.'s annoying cousin. In addition to possessing the same triple charge combo as Gurdy, he also has a bullet attack and spawns mooks. On early floors when your speed is low, there's a good chance one of his charges may connect.
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 in the original game, 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.
In Rebirth, Items that deal damage to you when used are rendered impotent if you have Isaac's Heart—this unfortunately makes Spark Plug useless, but you can now spam the IV bag without having to engage in door shenanigans.
Also in Rebirth, the Broken Remote will still work on infinite-use spacebar items (such as the Lucky Paw) even if they otherwise have no effect.
One of the most popular emoticons on Twitch is BibleThump, which is Isaac crying.
"It's not a won run yet!" tends to be used for very powerful runs, which came about due to Northernlion consistently saying it for runs which were very easy.
People messing around with the intro narration has resulted in The Isaac of Isaac. One of the Community Remix devs is currently making a mod that replaces all item textures with Isaac, turning this masterpiece into a playable experience.
CHUB DISLIKES SMOKE!explanation The Rules Card item is infamously useless. It's supposed to give the player hints, but not only is the hint in question (which seems to be the only thing the card ever pays out with, despite there being confirmed to be a ton of other, more useful hints for other things such as Boss Rush) referring to something rather obvious, very few people play the game without visiting the wiki anyway.
Moral Event Horizon: Isaac's mom crosses it at the start of the game with her attempt at filicide.
Most Annoying Sound: Isaac's 'hurt' sound when he takes damage has no variation and if you have to hear it several times in a row it quickly becomes grating.
Nausea Fuel: The environments and enemies are all really gross, from the giant turds lining the floors, the enemies that look like giant anuses firing out laser beams, grotesque monsters lined with all manner of horrific markings... ich. The Rebirth remake adds more details, including things like tiny maggots crawling around the floor in large numbers.
The Womb's music track in Rebirth, "Viscera", contains... indescribable fleshy sounds that might be a little unnerving to some players.
The Sacrifice rooms, where you give up health to get some random chest, are almost entirely useless and feel like a leftover. Rebirth did add a somewhat useful purpose to them, but it's almost pointless since knowledgeable players avoid them like the plague.
In the original game, the Polaroid trinket is needed to enter the Chest. Unless you have Mom's Purse to double your trinket capacity, this means sacrificing a potentially useful trinket for four levels in order to use it. Rebirth mercifully fixed this by turning it into a passive collectible, though this comes at the cost of Mom dropping a potentially useful item (though, if you get the Boss Rush, that can make up for it).
The Headless Horseman and Conquest, for players trying to assemble Meat Boy/Bandage Girl. Both count as Horsemen but only drop their respective Pony item, instead of a meat cube/bandage ball. On the same subject, the addition of Bandage Girl in Rebirth makes getting either achievement twice as hard, because now neither one is guaranteed to drop.
And just in case the quest wasn't hard enough, in Rebirth, sometimes your biggest savior can't even help you. The Book of Revelations no longer exists in the Shop's item pool, and using it won't cause a Harbinger to spawn if the floor contains a Double Trouble! boss (or Mr. Fred, as he takes up two rooms). For many a player, their run of resetting for a Basement I BoR was ruined by two Gurdies in the Womb. (Fortunately, summoning Meat Boy and Bandage Girl through the Monster Manuel counts towards the achievement, so if you have a way of guaranteeing rerolls then it's simpler to simply spam that instead.)
In Rebirth, the shop donation machine, which is used to upgrade the shop and unlock two items, only accepts so many coins before it shuts off and can't be donated to again until your next run. This can stifle a lot of progress towards upgrading it, especially if you chance upon a Dollar with nothing to use it on.
Rebirth added several new curses. While most are not a problem (and the first floor Labyrinth curse now leaves both Treasure Rooms unlocked), Curse of the Blind is absolutely terrible. The curse has the effect of making you unable to see the pedestal items on that floor, replacing them with a question mark icon. This can screw a run in so many ways it's not even funny. Treasure Room items become a gamble that can have you pick up something terrible like My Reflection, Devil Room items run the risk of saddling you with the Dead Cat on top of costing the health you paid for it, shop inventory costs you 15 coins for something you can never use... the whole floor essentially becomes a roulette wheel you can either try for potential help or ignore for a lost floor of items.
Four of the challenges have the Blindfolded mechanic, which completely disables Isaac's ability to fire tears, including Mom's Knife. Not only does this make killing enemies a lot more difficult, all of the associated challenges saddle you with terrible loadouts. Solar System is nothing but orbitals, which have poor range. Cat Got Your Tongue only gives you Guppy's Hairball as a weapon, which is unwieldy at best. Beans! forces you to rely on bombs, which means your run may potentially be ruined if you run out. The Family Man gives you three familiars, but they have a slow rate of fire and you have to beat Isaac with them.
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. Some combinations using it will screw you even harder, such as combining it with IPECAC or Bob's Rotten Head, causing your explosive projectiles to boomerang right back at you. Even worse is that the Suicide King challenge in Rebirth sticks you with the My Reflection + IPECAC combo for the entire run.
Bob's Brain and BBF in Rebirth. There's nothing worse than being in the middle of combat and having them respawn and explode on top of an adjacent enemy, catching you in the blast. Sometimes, BBF can even damage you as soon as you enter a room!
The Cursed Eye. While the quadruple charge shot is nice, if you are hit while charging the shot, you will be teleported to a random room. This makes fighting bosses very problematic, as even one mistake can warp you away and ruin all of your progress. Fortunately, this drawback is easy to work around, and can even be beneficial in some circumstances. Most notably, allowing you to take a free item from the Boss Rush room.
Rebirth offers a particularly odd candidate among the Challenge Gamers of the community: The Stop Watch. It permanently induces the slow effect on every enemy in the game, including the bonus of severely hampering the range of their projectiles, upon picking it up. Many players consider a run too effortlessly easy to bother finishing upon acquiring said item.
The No Damage Run achievements. At least they're mercifully divided into groups, so you don't have to go through all eight in one run.
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. Rebirth made the Womb somewhat more difficult by adding pits.
Rebirth ups the ante on that one with Dead Boy, achieved by completing one of the game's Brutal Bonus Levels, The Chest, or the Dark Room, without taking damage. Here's hoping you packed a Holy Mantle... though it is slightly easier on The Chest, as four free (as long as you have keys) items are available from the starting room, and there's a chance to find more after completing every vicious room.
Rebirth has The Lost. Unlocking it is a massive Guide Dang It and a Luck-Based Mission for the first part, though you can mercifully use seeds. Then, once actually unlocked, you have to do no damage runs of the entire game through both Brutal Bonus Levels (Mega Satan is optional) and the boss rush, and then do it all again on Hard mode to unlock the Godhead.
Assembling Super Meat Boy and Bandage Girl in Rebirth. In vanilla Isaac and WOTL, assembling Super Meat Boy wasn't too difficult to do as long as you got the Book of Revelations early enough. And you didn't have to assemble it to get the achievement, just kill all 4 of the Harbingers in one run. Unfortunately, the Book of Revelations no longer guarantees a Harbinger boss fight, instead giving a higher chance to run into them. The real kicker is that they now drop a Cube of Meat or a Ball of Bandages, so you have to hope the first one drops the item you want. Running into the Headless Horseman or Conquest will also ruin your chances of getting the achievements. Counter-intuitively, these achievements are actually easier if you go out of your way to avoid unlocking Conquest (which requires getting ten Angel Room items). Once Conquest is unlocked, it becomes downright impossible to manage a fair playthrough where you get the whole set. It's considered a lot less luck based just to set up a way to infinitely recharge the Monster Manual to get a level 4 Meat Boy/Bandage Girl. It says something that these achievements have a lower completion rate than almost every other achievement in the game, second only to the shop unlocks and all of the Lost's achievements.
The Suicide King challenge in Rebirth. Have fun playing the entire game with exploding tears that boomerang right back in your face!
Collecting all of the items for Platinum God and Real Platinum God in Rebirth is far more annoying than in the original. This is mostly due to two reasons: the Secret Rooms and Steven. Secret Rooms have a much greater variety now, most of which do not contain items, which combined with a larger number of exclusive items means it is that much more difficult to get everything from that pool. Most resort to Loophole Abuse with the D6, Judgement cards, and mushroom drops. Steven is a hundred times worse, because it has been removed from every item pool it was in in the original. The only way to get it is through the already rare Steven boss fight, and Little Steven has a drop rate five times greater than Steven. Rerolling Little Steven won't work, either; it either drops or it doesn't. The only way to guarantee the drop is to get Little Steven in a first floor treasure room then fight Steven, which is so rare as to be nearly impossible.
Mom's hand during the Mom boss battle, not to be confused with the Mom's hand monster in Rebirth. It comes out to swat you if you hang around the doors too much, and is near-instantaneous. It's avoidable, but you probably won't manage to do it on purpose. Playing as The Lost? Game over.
The Bloat's brimstone attack, which once again has no tell and hits almost instantaneously. And he'll use it without fail if you get in range.
Mama Gurdy's spike attack, where she raises up spikes in seemingly random areas of the room. Hope that you remembered to have flight or play as Azazel/The Lost!
The Adversary's Brimstone attack. It's telegraphed by a unique roar, but that's of little comfort when the beam actively curves to hit you. While it is possible to dodge by getting close and circling the boss, this attack becomes a terror when two Adversaries are in a single room and the one in the other corner unleashes the beam.
Mega Fatty, an otherwise easy to dodge if spongy boss, has one really annoying attack. He can, with almost no warning, leap from his current position to where you're standing in less than a second, which is practically undodgeable if you're standing still.
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. Rebirth mercifully toned this down by making his troll bombs solid, and boss fights with him usually have indestrcto-blocks to stop the bombs.
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 (or the Dark Room in Rebirth), always have more than one heart in case he turns up unannounced.
Gurdy Jr. Not so hard right? Then she charges at you with ridiculous accuracy. 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, Gurdy Jr. is one tanky boss. Rebirth's Double Trouble mechanic can actually saddle you with four of these guys at once.
Several of the Harbingers and Horsemen qualify. They all drop Cube/Bandage familiars (or Pony items) without fail, which can be annoying if you need a health up.
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 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. He's even worse in Rebirth, as his ipecac blasts are faster.
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. And the blood trails stick around for just enough time that you will step on one after completing a circle around the room. If the Ovum isn't dead or close by then, and you lack flight, you are very screwed.
The Haunt, added in Rebirth. At first, he's completely invincible and relies on his three smaller ghosts to assist him, but once they're killed he starts his attacks. The Haunt is actually very fast once he starts attacking, making it difficult to lead your shots to him, though he has relatively little health. Not only does he have an untelegraphed bullet spread attack, but he can also fire a Brimstone laser vertically across the screen with barely a second of warning. And if you think you can just run off to the side of the Haunt to dodge this, think again. Doing this causes him to charge you for a full heart of damage. Oh, and a boss room in the Depths may rarely contain two of them at once. And the best part? He's a Cellar boss, meaning he can potentially be the first boss encountered in a run. Some fans have come to the conclusion that he's even harder than the Widow, the previous infamous Cellar boss.
Rebirth also introduces The Adversary, the advanced version of the Dark One. The one and only thing that stands out about the Adversary is that he fires a Brimstone laser that homes in on you. This becomes incredibly problematic if there happens to be two of them in one room, as it gives you almost no room to dodge one Adversary's laser while avoiding the other Adversary's own attacks. If one of the Adversaries manages to wander into one of the corners, you're toast.
The Cage, which is pretty much an oversized Vis. For starters, he has the highest health of any boss in the game (with the exceptions of the final bosses), higher than that of Gurdy and even Mom. As for his choices of combat, he possess a rolling attack that is similar to Gurdy Jr's charge but without the ability to slow the boss with knockback. The real show-stopper, however, is his jump attack that sends out waves of stone that curve completely randomly and are impossible to predict. And yes, there's the chance of seeing two of them in one room in the final levels.
Carrion Queen can be difficult not because the boss herself is strong, but because she leaves behind damaging red poop that quickly regenerates if destroyed. On top of that, much like Scolex, only her end segment is vulnerable to attack (though getting her to swallow bombs works, too). If you don't damage her fast enough to trigger her second phase, the arena will be a minefield. The champion version is actually better, because she instead poops out tiny heart enemies which are easy to kill. She's both a blessing and a curse during the boss rush, in which her poop can blend into the all the bloodstains and become almost impossible to see, but will also cause major damage to the other bosses, potentially killing them in a few seconds.
If your speed is abysmal enough (like starting with Magdeline,) then bosses that chase you at high speed like War, The Fallen and Lust can be an absolute nightmare.
That One Level: The Cellar can be a much harder starting point than The Basement, usually involving harder enemies and rooms with a borderline fetish for spider enemies. In addition these levels can frequently stick you facing either The Widow or The Haunt as your first boss battle of the run.
Necropolis. Not only is it home to quite a few Demonic Spiders (such as Hangars and Masks + Hearts) and numerous spike traps, but it also holds some very annoying bosses like The Bloat and The Mask of Infamy. Fortunately, the latter only applies for Necropolis 1, as Necropolis 2 always has Mom as the floor's boss. There's still the risk of them spawning in Boss Challenge rooms, though.
Eve, too, to a lesser extent. She starts the game with below average health and damage, and her initial abilities are all essentially Cast from Hit Points. Do the math. It's so bad that, before the DLC, the Lethal Joke Character actually had a higher completion rate, despite being more joke than lethal.
Rebirth gives both of these characters buffs. Samson now starts with three hearts and his damage stacks don't reset until he leaves the floor. Eve's Whore of Babylon will trigger at a full heart instead of half a heart (it still triggers at half a heart for everyone else). Cain, however, was hit hard with the nerfbat, as his Lucky Foot no longer recycles bad pills.
Rebirth introduces Azazel, who is sometimes despised for being too powerful. To explain, he starts with three black hearts (but can acquire regular health through powerups), flight, and a short-range Brimstone attack. The range issue is at best minor, and Azazel can clear rooms like nobody's business. With a little skill, Azazel can easily make it all the way to Mom in time for the Boss Rush without any significant powerups. With powerups, he's a murder machine.
Invoked with The Lost. He can fly, but he's a One-Hit-Point Wonder and doesn't even start with any items besides one measly coin. The fact that one of his item unlocks requires you to beat every final boss (save for Mega Satan) on hard certainly does not help matters.
In terms of items, the Stopwatch. As mentioned above in Scrappy Weapon, The Stopwatch slows enemies and their projectiles, making the game so trivially easy to the point where it's not fun.
Urban Legend of Zelda: There are rumors floating around that beating the game five times with ??? unlocks Moses, who can turn enemies into money. No such character exists.
A rumor around the time of Rebirth's release was that a giant, undead version of Gurdy called Ur-Gurdy would replace Satan as the final boss of Sheol on rare occasions. It had an entry on the Rebirth wiki and on the character page here, but since then it has seemingly been proven to be fake.