Ascended Meme: The Rebirth is Cancelled joke that Northernlion and his friends started can be one of the messages that you get from fortune tellers. A bit ironic, since NL discredited the meme because Fan Dumb who couldn't read the sarcasm started giving the devs shit over it.
The Bloat is one of the most hated bosses in the game, to the point of having a subreddit dedicated to hating him. In the April's Fool challenge added in Afterbirth+, every single boss is replaced with him, with the only way to get rid of him for a floor is to have your active item act as the Book of Revelations, which still overrides the boss with a Horseman.
Creator Backlash: Edmund was reportedly pretty disappointed at how the Lost was discovered. Not because it was found quickly, but because people found it by datamining the game, rather than the community figuring out the cryptic hints in-game piece by piece. With the later Afterbirth expansion, Edmund countered this by patching in secret material when the community solved the puzzle: it wasn't even present in the game code until it was unlocked!
As the game doesn't give you the names of normal enemies until the credits (or at all in Rebirth outside Afterbirth+'s Bestiary), players tend to give them these. Anyone who has watched Northernlion enough tends to use "human popcorn", "silkworms", "Conga Line" and "zambies", in place of their real names (Mulligan/Host, Butt Licker, Charger/Spitter, Knight).
Meatboy Lvl. 5 — That's what some players call the severed body "generated" by The Shears. The reason behind it is because it used to be possible to have it constantly following you by acquiring five Meat Cubes via glitch exploitation.note It's still possible to acquire more than 4 Meat Cubes, but now the fifth one you get transforms into a new rotating Meat Cube instead of upgrading your 4th Lvl. Meatboy.
An even more common one is "Blue Baby" for the unwieldy ???. For the True Final Boss as well as the character. This was ascended as of one of the updates, with his will being signed as "???? (a.k.a. The Blue Baby)"
Pooters are known as "Grandfather Flies" because their white abdomens look like beards.
The Vis and its brethren are known as "vaginas" for obvious reasons.
Judgement for the Beggars (with the "Demon" and "Key" prefixes added when necessary), because they spawn from the Judgement card.
<weapon_name>tammy for Tammy's Head combined with a tear modifier in Rebirth, the most known being Brimtammy.
The True Final Boss of Rebirth has such an unintentionally ridiculous name that fans decided to make it more ridiculous by calling him Mega Stan.
Many fans call the Monster Manual "Monster Manuel" instead. This is an interesting case — in the original game, it actually was the Monster Manuel due to a typo. Some fans, due to either not realizing it was fixed in Rebirth or due to finding the typo hilarious, still call it Manuel.
Many players also refer to Mega Maw as "Mega Man", whether they meant to or not.
Hey, It's That Sound!: The sound effect for picking up coins in Rebirth is practically identical to the sound effect for picking up gold in Spelunky.
I Knew It!: The game taking place in Isaac's imagination was old news among fans long before the final ending actually revealed it.
The item Cancer (the zodiac sign) and the trinket Cancer (the disease).
The bosses Little Horn and Brownie have the same names as bosses in Super Meat Boy.
"Pay to play" has been used thrice: as the description of Magic Fingers, as the name of a Rebirth challenge, and as the name of an item introduced in Afterbirth. There's also the special seed "FREE 2PAY".
One of Us: Possibly, since one of the Challenge names in Rebirth is Glass Cannon, which starts the player off as Judas (who has one heart) with the Book of Belial, Loki's Horns, and Epic Fetus. And let's not forget the Glass Cannon item too.
Promoted Fanboy: Spider, the mind behind the SpiderMod program (a modified version of Isaac that runs in a separate .exe, is more optimized, and adds a number of features including various cheats and controller support) was hired to do coding work for the remake. Afterbirth then introduced an item named Spider Mod, giving all enemies individual health bars and showing how much damage your tears do to them, which was one of the functions introduced by SpiderMod.
Missing HUD, a popular mod for Afterbirth that gives you a more complete breakdown on your stats (including your devil deal and angel room chances), was made into an official feature in Afterbirth+, called Found HUD in the options.
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 been proven to be fake.
Spectacularly played with by both Edmund and the fanbase with Afterbirth. Fans seemed to notice that several items in the game were missing, and the devs as well as certain game elements seemed to imply this was intentional, leading to a massive hunt for the expansion's ultimate secrets. Fans would come up with long sequences of events to perform in order to unlock new content, sometimes in seriousness and often in parody of this very trope.
Players still sore from the previous nerfs and annoyed by the new hazards and penalties introduced in Afterbirth+, including how the game unlocks half soul hearts if the player reloads a run several times, began talk of how a supposed "Forget Me Never" item would, of all things, erase the player's save file. But that would be too much, right?
Sleeper Hit: Word of God has stated he never expected Isaac to be so popular. At one point he considered giving it away because he didn't believe anyone would actually want to spend money on something so weird and dark.
What Could Have Been: In this Northernlion run,which is co-commentated by Edmund,he states that "There would be some new rare items that cost 20 coins" in the (Then upcoming) DLC (Wrath of the Lamb). Come the expansion (And beyond that into Rebirth and its own expansions),and the most costly item in the shop is still 15 coins.
Edmund also mentioned that there would be a "new Lemon Mishap-like item,but better",though since no name was given,it's unknown if the item did make it in (Such as Holy Water) or not.
Given that Edmund is a Teasing Creator,however,the above may have never been considered in the first place,and were said only as a tease.
Word of God: Some information can be gleaned from McMillen's Tumblr blog and (now defunct) Formspring, though also be prepared for a fair bit of Teasing Creator.
Edmund has revealed that Isaac is Steven, thus making TBOI the prequel to TIME FCUK. Although, this piece of trivia should be taken with a grain of salt, since Edmund is known to be a tease. It most likely has more to do with said games sharing similar themes in the narrative, with Isaac and Steven choosing to go into their boxes, but only Steven choosing to come out.
With Edmund's guest appearance in a Roundtable stream, he confirmed that the game's narrator, who voices the introduction and occasionally calls out pills/cards, is supposed to be Isaac's dad (or at least a hallucination of him).