The story takes place in post-World War III San Francisco in December 2042. After the nuclear war, many major cities were rebuilt as New San Francisco, while some areas remained as Old San Francisco. The war also created two classes of citizens: Norms, who have a natural resistance to radioactivity, and Mutants, who are often forced to live in the run-down parts of the city.

Tex Murphy lives on Chandler Avenue in Old San Francisco. He is a Norm, but most of his friends are Mutants. As a private investigator, he has recently divorced Sylvia, is out of work, and is short on cash.

Tex finds work after a pawnshop across from his apartment is burglarized. He later takes a job from Countess Renier, who asks him to find her missing statuette. What begins as a promising case soon leads him to a doomsday plot by a cult called the Brotherhood of Purity.