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.
During her travels, Jo also encounters many men who quickly become entranced by her, often to fanatical degrees. They become entangled in her escapades, possibly as guardians, collaborators, and lovers. A motif of the series is how these men pay dearly for becoming involved with Jo.
The narrative jumps back and forth between different time periods and points of view, primarily Jo and the men entranced by her. The majority of the action in the first story arc takes place in the 1950s, the second in the 1970s, the third during the 1930s and World War II, while the fourth arc is set in the 1990s.
A couple of issues featured stand-alone stories focused on "fatales" before Jo. Issue #12 tells the story of Mathilda in 13th century France, while Issue #13 tells the story of "Black" Bonnie in the Wild West. Aside from her powers, both women also shared striking physical similarities with Jo and found themselves pursued by the same cult.
Ed Brubaker and Sean Phillips received multiple Eisner Awards nominations for Fatale in 2013: "Best Continuing Series" (Brubaker and Phillips), "Best New Series" (Brubaker and Phillips), "Best Writer" (Brubaker), "Best Penciller/Inker" (Phillips), and "Best Cover Artist" (Phillips).
David Stewart received a 2013 Eisner award for "Best Coloring".