Cryptosporidium 138, made of more complete Furon DNA, is now taking his place and continuing to pose as the United States President. Reasons are left ambiguous, though it is highly likely that he died of old age as Cryptosporidium clones don't tend to live very long. In 1969, ten years after Destroy All Humans!, Cryptosporidium 137 is dead. A remake of the game, Destroy All Humans! 2 Reprobed, was announced on September 17, 2021. Two sequels were made Big Willy Unleashed and Path of the Furon, that were developed by Locomotive Games and Sandblast Games, respectively.

It marked the last game in the series that was developed by Pandemic Studios.

It was released on October 17, 2006, in North America. Destroy All Humans! 2 (also known as Destroy All Humans! 2: Make War Not Love as seen in the title screen) was a video game for PlayStation 2 and Xbox and the sequel to Destroy All Humans!.