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Shout Out: The Binding of Isaac
  • Super Mario Bros.:
    • The 1-up mushroom that follows you around is green with white spots.
    • The Magic Mushroom and the Mini Mush are direct references to Mario's Super Mushroom and Mini Mushroom.
    • The Bobby-Bomb walking bomb upgrade is a clear reference to Bob-Omb.
  • The Legend of Zelda:
    • The HUD and basic rooms are very blatant ones to The Legend of Zelda.
    • Many enemies are also reminiscent of Zelda enemies. The most noticeable are the Chargers (which behave like Ropes) and Knights (which behave like Darknuts).
    • Teleportation items may randomly send you to a room with a guy saying "I AM ERROR."
    • Wrath of the Lamb's candle is pulled straight from The Legend of Zelda.
    • The Stepladder from the original Zelda's functionally identical counter-part, simply called "The Ladder."
  • Meat Boy:
    • One of the endings: Isaac dresses as Dr. Fetus from Super Meat Boy, complete with the stage title theme from that game. Unsurprisingly, the ending gives you the Fetus in a Jar powerup. There's also a power-up called "Doctor's Remote," which is another reference to the character in question.
    • C.H.A.D. can appear as an alternate version of Chub.
    • Meat Boy himself appears as a familiar when you collect Cubes of Meat, and Wrath of the Lamb adds a "SMB Super Fan" circular saw item that transforms the player character into a Meat Boy lookalike.
    • The Larry Jr. boss is presumably related in some way to Larry from the second-to-last world of Super Meat Boy.
  • The Wrath boss is basically Bomberman. In addition, players will occasionally find a room styled after the mazes from Bomberman's multiplayer filled with bombs to collect.
    • Adding to this, an item is slated to appear in Rebirth that makes bombs explode in the Bomberman cross fashion.
  • Steven, a tiny head that grows out of your skull. He also appears as a boss.
    • His unlocking is the secret "something from the future", obtained by completing the basement 42 times.
    • For some reason, The Stinger of the final ending tells you to get in the box. In fact, Isaac's relation with the chest and who is inside it is reminiscent of Steven and the box.
  • A number of internet meme faces make an appearance, particularly the Forever Alone and Troll Face, with the latter appearing on bombs which are ready to go off. And let's not forget Shoop-Da-Woop!, which is a charged laser weapon. There is also an enemy type with a distinctive trollface that will split in half upon receiving enough damage, and the duplicates will split further into even smaller copies, demonstrating the spirit, as well as appearance of the trollface. In its smallest form, it becomes a Pokerface.
  • One enemy type is the same species as Gish. Gish himself can appear as a boss as well, and drops a baby version of himself (a familiar whose shots slow enemies) when defeated.
  • The "Pills Here!" message after picking up a pill is a shout out to Left 4 Dead.
  • One effect that pills can give you is "Balls Of Steel," which gives you 2 soul hearts.
  • The null effect for pills is "I found pills!", with the fake effect "And ate them". This is likely a throwback to an early LOLCat macro.
  • The "My Little Unicorn" item seems to be a shout out to My Little Pony.
  • The "Technology" upgrade is a clear reference to the Borg.
  • That fly that buzzes around your head to intercept bullets is Pretty Fly (for a White Guy).
  • A Shovel item that lets you skip a floor has the description "We Need To Go Deeper."
  • The Parasite power-up resembles the Parasite from the Flash-Game "The Visitor" from fellow Newgrounds contributor Zeebarf.
  • When going into the One-Winged Angel form accessible through one of Eve's starting items, the transformation is denoted by the phrase "What a whorrible night to have a curse."
  • One of Death's attacks is scattering spinning sickles all over the room, which fly towards the player.
  • One of the projectile upgrades is bloody tears.
  • One of the new items in Wrath of the Lamb is the Notched Axe, a pickaxe that can be used to break rocks. This is a double reference, shouting out to the Notched Pickaxe from The Elder Scrolls V: Skyrim, which was itself a reference to Minecraft and its creator, Notch.
  • The Chemical Peel item will give you a Harvey Dent makeover.
  • An item named "Telepathy for Dummies," looking exactly like any "For Dummies" book would look like.
  • One of the powerups you can get from the Devil Room in Wrath of the Lamb is "Spirit of the Night", which changes Isaac's face to look like the Magic: The Gathering card of the same name.
  • One of the messages you can get from the Fortune Teller is "Look to La Luna." This was the clue on how to find Reptile in the original Mortal Kombat game. Two others, "MARRY AND REPRODUCE" and "STAY ASLEEP", reference They Live!.
  • Subverted in the case of Gluttony. A lot of fans think that his appearance and the blood-laser that shoots from the stomach are references to Fullmetal Alchemist; HOWEVER, Edmund McMillen himself has stated several times that the resemblance is purely coincidental, because he has never watched (nor even heard of, prior to the game's release) Fullmetal Alchemist. Holy contrived coincidences, Batman!
  • The Necronomicon's cover (which looks like a distorted or disfigured face) is the same as in Evil Dead.
  • The Wire Hanger item is a reference to the film Mommie Dearest, in which an abusive mother screeches the famous quote: "No more wire hangers ever!"
  • One of the new items in Binding of Isaac: Rebirth, is the Ludovico Technique, which leaves Isaac's eyelids pulled back, as in the classic scene of Alex's reprogramming.
  • The faceless God in the Angel Rooms is a reference to Jack Chick.
  • The Beginner Deck item in Rebirth is a reference to Magic: The Gathering.
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