The family consists of Howard Cunningham, a hardware store owner, his homemaker wife Marion and the couple's two children, Richie, an optimistic if somewhat naive teenager, and Joanie, Ritchie's sweet but feisty younger sister. The Cunninghams also had an older son named Chuck, a character who disappeared during the second season.

The earlier episodes revolve around Richie and his friends, Potsie Weber, Ralph Malph and local dropout Arthur "The Fonz" Fonzarelli, but as the series progressed, "Fonzie" proved to be a favourite with viewers and soon more story lines were written to reflect his growing popularity. Soon Fonzie befriended Richie and the Cunningham family. The focus would also occasionally shift to other additional characters, such as Fonzie's cousin Chachi, who became a love interest for Joanie Cunningham.

This long-running show spawned several other television series, including Laverne & Shirley, Mork & Mindy, and Joanie Loves Chachi, and is currently a musical touring the United States.

Despite some inconsistencies, it is generally indicated that the events of the series begin in 1955 and, after eleven seasons, end in 1965. Most episodes take place about 19 years before the year of their first air date. The second season episode "The Not Making of the President" revolves around the 1956 presidential election, while the sixth season episode "Christmas Time" ends with a photo dated Christmas 1960. In the 10th season episode "Babysitting", Fonzie watches the first heavyweight championship fight between Cassius Clay and Sonny Liston on television. This boxing match occurred on February 25, 1964. In the first part of the series finale "Passages", Joanie and Chachi are wearing T-shirts that say "The Kinks – Summer 1965 Tour".

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