The series focuses on an eccentric motley crew that is the Smith family and their three housemates: Father, husband, and breadwinner Stan Smith; his better half housewife, Francine Smith; their college-aged daughter, Hayley Smith; and their high-school-aged son, Steve Smith. Outside of the Smith family, there are three additional main characters, including Hayley's boyfriend turned husband, Jeff Fischer; the family's man-in-a-goldfish-body pet, Klaus; and most notably the family's zany alien, Roger, who is "full of masquerades, brazenness, and shocking antics."

New York, early 1960s. Against the backdrop of a vibrant music scene and tumultuous cultural upheaval, an enigmatic 19-year-old from Minnesota arrives in the West Village with his guitar and revolutionary talent, destined to change the course of American music.