The novel explores the life of an African-American man, Macon "Milkman" Dead III, from birth to adulthood. Set against the backdrop of racial tension in the mid-20th century United States, it delves into his journey of self-discovery and understanding his heritage. As Macon embarks on a literal and figurative journey south to reconnect with his roots, he encounters various characters that help him understand his family history and the power of community. The narrative is deeply rooted in African-American folklore and mythology, offering a profound commentary on identity, personal freedom, and the destructive power of racism.

The book follows the life of Calliope Stephanides, a Greek-American hermaphrodite, who narrates her epic story starting from her grandparents' incestuous relationship in a small village in Asia Minor to her own self-discovery in 20th century America. The novel delves into themes of identity, gender, and the American dream, while also providing a detailed history of Detroit through the eyes of three generations of an immigrant family.