The Lunatic Cafe continues the adventures of Anita Blake. Anita attempts to solve a series of shapeshifters disappearances while exploring her relationship with Richard Zeeman, her werewolf boyfriend, and avoiding the advances of Jean-Claude, a vampire would-be paramour. As with its predecessors, The Lunatic Cafe blends elements of supernatural, hardboiled and police procedural fiction.

Within the novel, the "Lunatic Cafe" is the name of a restaurant that is operated by and serves as a base for St. Louis area shapeshifters. Hamilton continued the practice of naming the novels after a fictional location within each novel for most of the Anita Blake series.