The series was originally announced in the back of the final issue of Brubaker and Phillips' previous collaboration, Criminal: Last of the Innocent. Further details about the series, including its publisher, were revealed at the 2011 New York Comic Con. Brubaker also released a video teaser for the series.
Several issues featured an article written by Jess Nevins and others on the crime/noir characters, both fictional and real.
Fatale chronicles the life of Josephine, or "Jo", an archetypal femme fatale who is seemingly immortal, having survived from the 1930s to the modern day unaged, and also has a supernatural ability to hypnotize men into becoming intensely infatuated with her, whether she wants them to be or not.
Through the decades, Jo struggles to understand and control her powers while being pursued by a violent cult. The cult worships cosmic gods reminiscent of Lovecraftian horrors, which are somehow tied to Jo.