During early development, the series was titled You're the Boss before producers changed it to Who's the Boss? shortly before its 1984 premiere, choosing an open-ended title that suggested either lead character could be the one 'in charge'.

Tony Danza served as the original prototype for the Tony character from the start of development, whereas Judith Light had to audition against many other actresses to win the role of Angela.

The character of Mona was initially conceived as an older sister to Angela, but after struggling to cast that role, creators Cohan and Hunter rewrote her as a free-spirited, quick-tongued mother figure specifically envisioning Katherine Helmond for the part.

The show's pilot was filmed in November 1983, a full ten months before the series actually premiered on television in September 1984.

ABC originally planned to launch the show as a mid-season replacement in January 1984, but creative differences between the producers and the network delayed the premiere until the following fall season.

Who's the Boss? debuted on September 20, 1984, going head-to-head in the same time slot against the premiere of NBC's The Cosby Show.

Early reviews were lukewarm, with one critic comparing Danza and Light's on-screen chemistry to Katharine Hepburn and Spencer Tracy, while The New York Times questioned whether Danza's frequently shirtless, muscular physique would help sustain the show's ratings.

The series finale deliberately avoided the widely expected marriage between Tony and Angela, ending on an ambiguous note instead; this was partly due to network concerns that a definitive ending like a wedding could hurt future syndication, and Tony Danza himself strongly opposed the marriage, feeling it would contradict the show's original premise.

The theme song 'Brand New Life' was performed by three different singers over the show's run—Larry Weiss (1984–1986), Steve Wariner (1986–1990), and Jonathan Wolff (1990–1992)—and its opening lyric was changed starting in season three from 'There is more to life than what you're living' to 'There's a time for love and a time for living.'

A 1987 backdoor pilot spin-off attempt, 'Charmed Lives,' starring Fran Drescher and Donna Dixon aired as the season two finale but was not picked up as a series.

A planned 1987 spin-off called Mona, which would have had Mona leave to help run a seedy Manhattan hotel with her brother, was set up in a season three two-part episode, but ABC got cold feet about losing the character, forcing the writers to rewrite the ending so Mona returned home.

In the Italian dubbed version, Katherine Helmond's character Mona was renamed Moira because 'mona' is a vulgar slang term for female genitalia in Italian.

The German adaptation Ein Job fürs Leben reused the original American scripts almost exactly and replicated the original set design, only changing minor details like paintings and decor to fit a German style, despite renaming the characters and relocating the setting to Hamburg.