Unlike the game's predecessor, Rebirth has a limited multiplayer mode, allowing an additional player in Rebirth, later increased to three additional players in Afterbirth and Afterbirth+. The player defeats monsters, using Isaac's tears as projectiles, and collects items which modify his appearance, attributes, and abilities, potentially creating powerful combinations. When Isaac's mother is about to kill him, he escapes to the basement and fights through random, roguelike dungeons. The player controls Isaac, a young boy whose mother, convinced that she is doing God's work, strips him of everything and locks him in his room. Similar to the original The Binding of Isaac, the plot is based on the biblical story of the same name and was inspired by McMillen's religious upbringing.

The third, Repentance, was released in March 2021. Afterbirth and Afterbirth+, in October 2015 and January 2017, respectively, with more game content and gameplay modes Afterbirth+ also added support for user-created content. This platform had limitations and led McMillen to work with Nicalis to produce Rebirth with a more advanced game engine, which in turn enabled the substantial addition of content and gameplay features. Rebirth is a remake of The Binding of Isaac, which was developed by McMillen and Florian Himsl and released in 2011 as an Adobe Flash application. The PlayStation 5 and Xbox Series X/S versions were released in November 2021.

Rebirth was released for Linux, Microsoft Windows, OS X, PlayStation 4 and PlayStation Vita in November 2014, for Xbox One, New Nintendo 3DS and Wii U in July 2015, for iOS in January 2017 and for Nintendo Switch in March 2017. The Binding of Isaac: Rebirth is an indie roguelike video game designed by Edmund McMillen and developed and published by Nicalis.

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