Born Eloise Gwendolyn Sanford in New York City, New York to parents James Edward Sanford and the former Josephine Perry. Sanford was the first African-American actress to win a Lead Actress Emmy Award (for Outstanding Lead Actress in a Comedy Series in 1981), and has a star on the Hollywood Walk of Fame. She was a member of Alpha Kappa Alpha Sorority, and received an honorary doctorate degree from Emerson College in Boston, Massachusetts.

During the 1960s, Sanford worked in the theatre industry, and in 1967 she made her film debut in Guess Who's Coming to Dinner, playing the critically acclaimed role of the maid Tillie Binks. She caught the attention of major Hollywood players, including Norman Lear, who cast Sanford in the role of Louise Jefferson in All in the Family. She almost turned down the role after receiving a bucket of fried chicken in her dressing room, which in those days was a racist stereotype as a favorite food of African-Americans. Norman Lear assured her that it was a genuine gift, and she eventually agreed to play the part. Sanford and her TV husband, Sherman Hemsley, were so popular that The Jeffersons was spun off into its own series.

After production of The Jeffersons ended in 1985, Sanford realized that she and Hemsley were typecast by their Jeffersons' roles. Sanford was mostly limited to guest TV appearances and cameo appearances in movies, appearing in The Fresh Prince of Bel-Air, Dream On, Roseanne, Living Single, Hangin' with Mr. Cooper, In the House and The Steve Harvey Show, as well as the extremely short-lived 1992 CBS Hearts Are Wild (similar to Love Boat). She also did voice acting for The Simpsons in her final television appearance before her death.

She has also done several voices on three other cartoon shows including Wait Till Your Father Gets Home, A Pup Named Scooby-Doo and Pepper Ann.

Sanford also appeared with Sherman Hemsley in a series of advertisements for Denny's and Old Navy. Such was their compatibility and credibility as a married couple that no one seemed to notice or care that Sanford was twenty years older than Hemsley. She and Hemsley also made a cameo appearances in films such as Sprung and Mafia!

Sanford died on July 9, 2004 of cardiac arrest and heart disease at Cedars-Sinai Medical Center in Los Angeles, California. She was a month and a half away from her 87th birthday and was interred at Forest Lawn Hollywood Hills in Los Angeles.

For her contribution to the television industry, Isabel Sanford has a star on the Hollywood Walk of Fame at 7080 Hollywood Boulevard.

Kathryn Shattuck (13 July 2004). "Isabel Sanford, 86, Actress Who Portrayed Mrs. Jefferson, Dies". The New York Times. http://query.nytimes.com/gst/fullpage.html?res=9C06E6D81E3BF930A25754C0A9629C8B63&sec=&spon=. Retrieved 2008-03-19. 

Mary Tyler Moore (1976) · Beatrice Arthur (1977) · Jean Stapleton (1978) · Ruth Gordon (1979) · Cathryn Damon (1980) · Isabel Sanford (1981) · Carol Kane (1982) · Shelley Long (1983) · Jane Curtin (1984) · Jane Curtin (1985) · Betty White (1986) · Rue McClanahan (1987) · Beatrice Arthur (1988) · Candice Bergen (1989) · Candice Bergen (1990) · Kirstie Alley (1991) · Candice Bergen (1992) · Roseanne Barr (1993) · Candice Bergen (1994) · Candice Bergen (1995) · Helen Hunt (1996) · Helen Hunt (1997) · Helen Hunt (1998) · Helen Hunt (1999) · Patricia Heaton (2000)

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