A third expansion, Repentance, was announced in September 2018. Two expansions have been released, 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 new 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. A version for the Nintendo Switch was released on March 17, 2017. After an initial rejection due to its controversial content, Nicalis released Rebirth on iOS on January 11, 2017. Rebirth was released for Microsoft Windows, OS X, Linux, PlayStation 4, and PlayStation Vita in November 2014, and for Xbox One, New Nintendo 3DS, and Wii U in July 2015.

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The Binding of Isaac: Afterbirth is the massively updated expansion to 2014's roguelike of the year, The Binding of Isaac: Rebirth.

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