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• Bill Smitrovich as Andrew "Drew" Thatcher:

Drew is the husband of Libby Thatcher and the father of Paige, Corky, and Becca Thatcher. He is a Special Olympics coach who formerly worked for a construction company before going into the restaurant business.

• Patti LuPone as Elizabeth "Libby" Thatcher:

Drew's wife, Paige's stepmother, and Corky and Becca's mother, who has been a singer and actress. She is very supportive of Corky and proud that Corky and Becca take part in their church's drama group and that Becca is in her school's drama club. At the end of Season 2, she gives birth to her and Drew's third child, a son named Nicholas.

• Monique Lanier (season 1); Tracey Needham (seasons 2-4), as Paige Thatcher:

Drew's daughter, Libby's stepdaughter, and Corky and Becca's older half-sister. Paige frequently dates men of whom her father does not approve. She is very caring of Corky but has a love-hate relationship with Becca.

• Chris Burke as Corky Thatcher:

Corky is the middle child: younger brother of Paige and older brother of Becca. Despite having Down Syndrome, he takes mostly regular classes in high school. He occasionally struggles, and indicated that mathematics was his hardest subject, but he improves through tutoring sessions.

• Kellie Martin as Rebecca "Becca" Thatcher:

Becca is the younger sister of Corky and Paige. She is nerdy but attractive; at school, she is socially awkward, especially around her crushes, such as Tyler and Jesse.

• Tommy Puett (recurring, season 1; main, seasons 2-3) as Tyler Benchfield: Corky's best friend and Becca's first boyfriend. He dies from drinking and driving in his last appearance.
• Chad Lowe (recurring, season 3; main, season 4) as Jesse McKenna: Becca's second boyfriend.

Recurring

• Ray Buktenica (guest, season 1; recurring, seasons 2-3) as Jerry Berkson, Libby's boss at Berkson & Berkson, an advertising agency. Jerry is eccentric and somewhat egomaniacal; he never fails to show his temper, but Libby always stands up to him. Jerry later becomes a partner in Drew's restaurant, The Glen Brook Grill.
• Tanya Fenmore (seasons 1-3) as Maxie, Becca's best friend. Maxie leaves early in season 3 for a study-abroad in Paris and is never seen again.
• Michele Matheson (seasons 1-2) as Rona Lieberman, a popular girl at school who is Becca's rival and a love interest for Tyler.
• David Byrd (guest, season 1; recurring, seasons 2-4) as Hans, a chef who works at the Glen Brook Grill. He is a German immigrant.
• Mary Page Keller (season 2) as Gina Giordano, Libby's sister, who comes to live in the Thatcher household for a time.
• Leigh Ann Orsi (season 2) as Zoe, Gina's daughter, who comes to live in the Thatcher household for a time.
• Troy Evans (seasons 3-4) as Artie McDonald, a welding foreman and Paige's boss at Stollmark Industries. In season 4, Artie and Paige are laid off from the Stollmark factory and they launch a contracting business together.
• Lance Guest (seasons 3-4) as Michael Romanov, a welder and artist. He is Paige's co-worker at Stollmark Industries and becomes her love interest.
• Andrea Friedman (seasons 3-4) as Amanda Swanson, Corky's girlfriend, a college student. Like Corky, Amanda also has Down Syndrome. Early in season 4, Corky and Amanda elope, which comes as a shock to their families.
• Kiersten Warren (season 4) as Kathy Goodman, Becca's friend and co-worker at a bookstore. She is usually referred to by her last name only. A recent high school dropout, Goodman is convinced by Becca to enroll at Marshall High, which she does during their senior year, after having quit a previous school.

Guest stars

• Al Ruscio as Sal Giordano, Libby's father
• Penny Santon as Teresa Giordano, Libby's mother
• Gloria Gifford as Mrs. Kneffer, principal of Marshall High
• Gina Hecht as Angela, Libby's cousin, an attorney
• Rick Rosenthal as Richard Thatcher, Drew's brother
• Peter Van Norden (seasons 1-3) as Coach Paintz Kutner, a former classmate of Drew's
• Alan Blumenfeld (seasons 1-3) as John Khatchadourian, a former classmate of Drew's
• Whip Hubley as Dr. Oliver Matthews (season 1), the veterinarian that Paige works for, and as Coach Eric Bradford (season 2), a gymnastics coach at Marshall High.
• Michael Rankin as Donnie Benchfield, Tyler's younger brother who has Down Syndrome.
• Michael Alldredge as Mr. Seedling
• Alfred Dennis as Miller
• Shannen Doherty (season 1) as Ginny Green, a new student in school whom Corky has a crush on
• Adam Carl (season 1-2) as Matt Hardy, a friend of Becca's whom she briefly dates
• Viveca Lindfors (season 1) as Mrs. Doubcha, Becca's dance instructor
• Elyssa Davalos (season 2) as Doreen Gillespie, a waitress at the Glen Brook Grill
• Barney Martin (seasons 3-4) as Stan Baker, owner of the movie theater where Corky works
• Mitzi McCall (season 3) as Midge, a waitress at the Glen Brook Grill
• Dorothy Lyman (seasons 3-4) as Mary McKenna, Jesse's mother
• Steven Eckholdt (season 3) as Kenny Stollmark, Jr., son of the Stollmark Industries president. He becomes romantically involved with Paige and they nearly get married.
• Drew Snyder (seasons 3-4) as Bill Swanson, Amanda's father
• Charlotte Stewart (seasons 3-4) as Collette Swanson, Amanda's mother
• Ned Vaughn (season 4) as Eric, manager of the bookstore where Becca works. He has romantic feelings for Becca.
• Martin Milner (season 4) as Harris Cassidy, owner of the bookstore where Becca works
• Michael Goorjian (season 4) as Ray Nelson, a classmate of Becca's
• Christopher and Kevin Graves (season 4) as Nicholas Thatcher
• Richard Frank (season 4) as Chester, a patient that Jesse meets while being hospitalized for the effects of AIDS

Early seasons

During the show's first year, the main focus was on Corky. Much of the show examined the challenges of a family whose son had Down Syndrome. The Thatchers sought to have Corky interact with regular society after spending years socializing him amongst other kids with Down syndrome in "special" classes. The need to integrate Corky into normal society was Season 1's main storyline, as the Thatchers opted to enroll Corky in a regular high school despite the principal's demand that he be placed in an alternative program for those with Down syndrome.

In addition, during the first three seasons, episodes included Tyler Benchfield (Tommy Puett), Becca's high school crush, who also had a brother with Down syndrome.

Corky eventually got a job as an usher at a local movie theater. He later found a girlfriend, Amanda Swanson (Andrea Friedman), who also had Down Syndrome. They married by the series' end.

Later seasons

By the second season, the writers began to expand the show's scope beyond Corky, and the third and fourth seasons centered on Becca and a new character, Jesse (Chad Lowe), a junior who met Becca through the school's theatre department. As they become friends, Jesse told Becca he was HIV positive. Tyler became less prominent in Becca's life and was jealous of Becca's closeness with Jesse. His character was written out and he was given the memorable sendoff of dying in a car accident with Corky as passenger.

Much to the surprise of those around them, Becca and Jesse began a relationship despite his HIV. The writers explored life with HIV through Jesse's character, and the difficulties the disease causes with romantic relationships. The relationship between Corky and Becca, previously portrayed as close, was also explored, as Corky briefly turned his back on his sister for dumping a mutual friend to date Jesse.

The fourth season's first episode, in which a 40-something Becca (Pamela Bellwood) tours the house she grew up in while remembering the events of 25 years earlier, establishes that Jesse would ultimately die from AIDS and that Becca would move on and marry a man named David. The series itself ended ambiguously but on an upbeat note, showing Becca five years later, married with a son named Jesse. In the final episode Corky was set to graduate from high school, but he did not because the school board did not waive the math requirement.

Season 1 (1989–90)

Season 2 (1990–91)

Season 3 (1991–92)

Season 4 (1992–93)