Graysmith worked as a political cartoonist for the San Francisco Chronicle in 1969, when the Zodiac killer case came to prominence. He attempted to decode letters written by the killer and became obsessed with the case over the next 13 years. Graysmith wrote two books about the case; his 1986 book Zodiac was the basis for the 2007 film by the same name. He eventually gave up his career as a cartoonist to write five more books on high-profile crimes, one of which became the basis for the film Auto Focus (2002).

Graysmith was married to Margaret Ann Womack, a nurse, from 1963 to 1973. He then married Melanie Krakower in 1975, but they divorced in 1980. He directly attributes his failed marriage to his intense interest in the Zodiac case.