She was cast in the role of “Amy Cassidy;” a character that was funny, romantic, and exuberant— in the series Bosom Buddies, starring Tom Hanks and Peter Scolari. Following its cancellation in 1982, Sperber appeared in the comedy The First Time, and worked a year on the series Private Benjamin. She then resumed her feature work in the Tom Hanks theatrical vehicle Bachelor Party, directed by Neal Israel. Israel used her again in Moving Violations in 1985. That same year, she appeared as Linda McFly in Zemeckis’ highly successful Back to the Future. She reprised her role as Linda in Back to the Future Part III.

In 1983, Sperber married Richard Velasquez and had a son, Preston, in 1986, and a daughter, Pearl, in 1990. Pearl also goes by the name “Daphne”. The marriage ended in divorce in 1994.

Sperber’s roles grew larger in the wake of Back to the Future, and over the next decade she starred in the series Babes (a comedy about three zaftig women). In 1994, Sperber was cast in a major supporting part in the CBS-TV series Hearts Afire. By this time, she had lost a lot of weight. As far as acting roles were concerned, she preferred comedy. As she told TV Guide in 1990, “I’m an actress who likes to say something funny—everybody laughs and your job is done.” In 1998 she guest starred as April the cleaning lady and Grace’s muse on the twelfth episode of Will & Grace.

In 1997, Sperber was diagnosed with breast cancer, which seemed to go into remission following treatment. She revealed in April 2002 that the cancer had reappeared and spread throughout her body, and by mid-2004 she had undergone experimental brain radiation therapy. She continued to work in television and movies during this period, including episodes of Unhappily Ever After, Home Improvement, Will & Grace, Grounded for Life, and the movies Desperate But Not Serious (1999) and Sorority Boys (2002).

In 1998, Sperber also helped the United States Postal Service unveil and promote a breast-cancer stamp.

In addition to her work on TV and movies, Sperber also was the founder of weSPARK Cancer Support Center, an independent organization formed in 2001 to advance and help support individuals and their families fighting various forms of cancer through free emotional support, information and social events/activities. In addition to being the founder, Sperber also served on the board of directors and wrote the quarterly newsletter. According to one of the last known interviews with Sperber by Terra Wellington, the weSPARK organization was her key cause and effort in the last year of her life with her stating “The whole idea of weSPARK’s programming was that I didn’t want people to walk into a room and have a therapist ask how they feel. I wanted peer support.”

She died of breast cancer on November 29, 2005, at the age of 47.

Her last work was lending her voice to “Roger ‘n’ Me”, an episode of American Dad! that aired in 2006, after her death. The producers of the show renamed her character Wendie Jo in honor of the actress.