Femme Fatales was founded by Frederick S. Clarke in the summer of 1992, as the sister publication of his science fiction film magazine Cinefantastique. Published by Clarke, it was originally edited by pin-up photography collector and expert Bill George. It focused on science fiction, fantasy, and horror actresses, from B-movies to Academy Award winners, featuring provocative non-nude photography pictorials, alongside extensive career interviews. It was unique in that it encouraged contributions from the actresses themselves, and featured articles penned by scream queens Brinke Stevens and Debbie Rochon, amongst others. It was a publishing success, at one time producing an issue every three weeks.
Clarke committed suicide in 2000, and for two years, both magazines were published by his widow, Celeste Casey Clarke. At the end of 2002, Femme Fatales was published bi-monthly, and had an unaudited circulation of 70,000. In 2002, she contacted Mark A. Altman, the president and chief operating officer of Mindfire Entertainment, a science fiction writer and producer, the former editor-in-chief of the fanzine Sci-Fi Universe and a regular contributor to both magazines, allowing Mindfire to take over their publication. David Williams, a former executive features editor at the Hollywood Reporter, became editor-in-chief of both publications. Both magazines' operations were moved from Chicago to Culver City.
Williams planned the 2003 revamp of Femme Fatales as a version of the men's magazine Maxim focusing on actresses in science fiction and horror films.
In 2011, the magazine was turned into a hit television series, evoking the spirit of classic film noir and pulp fiction for Cinemax.