The series stars Sarah Silverman, Laura Silverman, Brian Posehn, Steve Agee, and Jay Johnston. Silverman plays a fictionalized version of herself, an unemployed, immature woman who leads an irresponsible life. Her most notable trait is her undiluted, childlike self-absorption, which commonly leads to awkward situations in which she insults friends, family and total strangers indiscriminately. Laura Silverman plays her responsible sister of the same name, who takes care of Sarah, despite the chaos she brings down around them. Laura pays Sarah's rent and helps her out in most situations.
Posehn and Agee play Brian and Steve, a gay couple who are Sarah's neighbors and friends. Sarah, Laura, Brian, and Steve all hang out in a group and frequently eat together in a coffee house called Joseph's. Laura is dating Officer Jay (played by Johnston), a police officer, whom she meets in the show's first episode when Sarah is charged with a DUI, after which he joins the ensemble. Laura and Jay seem to be in love with each other, and Jay certainly makes an effort to be kind to Sarah whenever he can. However, Sarah is jealous of him because she fears that Laura is replacing her with Jay. Despite Jay's kindness, Sarah vows to destroy him. All of the main characters live in Valley Village, California, a district in the San Fernando Valley portion of Los Angeles.
The show features Sarah Silverman performing comedic songs in between some scenes. Silverman's comedy usually revolves around ethnic stereotypes, toilet humor, and similar taboo humor about modern life, which mirrors her real-life standup act. Adding to the humor is the cognitive dissonance between Sarah's apparently cute and harmless appearance and the character's vast destructive capacity. Each episode begins with Sarah presenting a brief slideshow overview of her life and the various people in her life. Most episodes end with Sarah, back in bed at her apartment, comically explaining (to her dog) what she has learned from the episode's events.