- Judith Light appeared in Season 2 as a colleague of Steven, unsuccessfully attempting to seduce him.
- Tom Hanks appeared during the first and second seasons as Elyse's alcoholic younger brother Ned.[4]
- Geena Davis portrayed inept housekeeper Karen.
- River Phoenix played a fourteen-year-old math genius who develops a crush on Jennifer after coming to tutor Alex. Phoenix's sister, Rain, would also appear as one of Jennifer's friends in a different episode.
- Courteney Cox played Alex's girlfriend Lauren at the end of the series
- Julia Louis-Dreyfus portrayed a lawyer in the two-part episode "Read It and Weep", which was about Jennifer's book being banned.
- Crispin Glover played one of Alex's friends on the episode "Birthday Boy". Glover had played George McFly, the father of Michael J Fox's character Marty McFly in the originalBack to the Future in 1985.
- Wil Wheaton played the target of Jennifer's affection; she played dumb in order to convince him to date her.
- Corey Feldman played a 7th grade classmate of Jennifer who was a nominee to win the Thomas Dewey best student achievement award on the episode "The Disciple".
- Jeff Cohen played 2 different characters; Marv Jr. on the episode "The Visit", and Dougie Barker on the episode "4 Rms Ocn Vu".
- Christina Applegate played Kitten, a member of Jennifer's band, on the episode "Band on the Run".[6]
- Stephen Baldwin appeared as a member of a therapy group that Alex attends with his girlfriend.
- Daniel Baldwin appeared as an army recruit who harasses Skippy.
- Joseph Gordon-Levitt played Dougie, a kindergarten friend of Andrew in two episodes, "Sign of the Times" and "Father, Can You Spare A Dime?"
- Jane Adams played Marty Broadie in two 7th season episodes, "They Can't Take That Away from Me: Part 1" and "They Can't Take That Away from Me: Part 2".
- James Cromwell played John Hancock in the 3rd season episode "Philadelphia Story".
- John Randolph played Jacob Keaton, Steven's father, in "I Never Killed for My Father". He was revealed to be dead in "Remembrance of Things Past, Parts 1 & 2".
- Timothy Busfield played Doug in two 1984 episodes ("Best Man" and "Little Man on Campus"), and "Young Matt" in a 1986 episode ("My Back Pages").
- Hank Azaria played a co-worker of Mallory's in the season 7 episode "Designing Women".
- David Faustino played Keith Bailey the son of a divorced family friend who was taken away from his mother by his father in the episode "To Snatch a Keith".
- Danny Nucci played a school bully who got beaten up by Jennifer after harassing her boyfriend at school in the episode "Designated Hitter".
His wife is Tracy Pollan who appeared on the show.