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The show stars Peter Krause as Nate Fisher, whose funeral director father (Richard Jenkins) dies and bequeaths ownership of Fisher & Sons Funeral Home to Nate and his other son David (Michael C. Hall). The Fisher clan also includes widow Ruth Fisher (Frances Conroy) and daughter Claire Fisher (Lauren Ambrose). Other regulars include mortician and family friend Federico Diaz (Freddy Rodriguez), Nate's on-again/off-again girlfriend Brenda Chenowith (Rachel Griffiths), and David's long-term boyfriend Keith Charles (Mathew St. Patrick).

On one level, the show is a conventional family drama, dealing with such issues as interpersonal relationships, dysfunction, infidelity, personal growth, and religion. At the same time, it is distinguished by its focus on the topic of death, which it explores on personal, religious, and philosophical levels. Each episode begins with a death, the cause of which ranges from heart attack to murder to accidental death or sudden infant death syndrome. That death usually sets the thematic tone for each episode, allowing the characters to reflect on their current fortunes and misfortunes in a way that is illuminated by the death and its aftermath. The show also uses dark humor and surrealism throughout its seasons.