Eventually Ponsonby betrays Crypto, revealing he is the leader of the British branch of Majestic, Majestic Sector 16. They discover that the KGB have created a type of spore that causes humans to mutate into monsters.

After saving Bay City from annihilation at the hands of the Soviets, Crypto discovers that the KGB have fled to Albion and promptly follows, where he meets Reginald Ponsonby-Smythe, the James Bond-esque head of M16 (a parody of MI6), and a rogue KGB agent named Natalya Ivanova. Crypto's commander, Orthopox 13, downloaded his consciousness into a holographic unit (called a HoloPox Unit) just before he died. Not only must Crypto stop the KGB from destroying America, he desires revenge for the destruction of the mothership. Soon after, Crypto's new adventure begins. Seeing the Furons as a threat to the Soviet Union, the KGB destroy the Furon mothership with a nuclear missile. KGB intelligence reveals that Crypto-138 is the first and only Furon to have genitalia, referred to only as 'The Package'. His clone, Cryptosporidium-138 (Crypto for short), made of more pure Furon DNA, is now taking his place and continuing to pose as the United States President. The game begins with a KGB slide show meeting showing that the main character from Destroy All Humans!, Cryptosporidium-137, is now deceased for unknown reasons.

The game is set in 1969, 10 years after the original.

Destroy all humans blisk