Drescher was born in Kew Gardens Hills, New York, the daughter of Sylvia, a bridal consultant, and Morty Drescher, a naval systems analyst. Her family is from Southeast and Central Europe. Her maternal great-grandmother Yetta was born in Focsani, Romania, and emigrated to the United States, while her father's family came from Poland. She has an older sister, Nadine.

In the 2000s, Drescher made a return to television both with leading and guest roles. In 2003, Drescher appeared in episodes of the short lived sitcom, Good Morning, Miami as Roberta Diaz. In 2005, she returned with the sitcom Living with Fran, in which she played Fran Reeves, a middle-aged mother of two, living with Riley Martin (Ryan McPartlin), a man half her age and not much older than her son. Former Nanny costar Charles Shaughnessy appeared as her philandering ex-husband, Ted. Living with Fran was cancelled on May 17, 2006, after two seasons.  In 2006, Drescher guest starred in an episode of Law & Order: Criminal Intent; the episode, "The War at Home", aired on US television on November 14, 2006. She also appeared in an episode of Entourage and in the same year, gave her voice to the role of a female golem in The Simpsons episode "Treehouse of Horror XVII". In 2007, Drescher appeared in the US version of the Australian improvisational comedy series Thank God You're Here.  In 2008, Drescher announced that she was developing a new sitcom entitled The New Thirty, also starring Rosie O'Donnell. A series about two old high school friends coping with midlife crises, Drescher described the premature plot of the show as "kind of Sex and the City but we ain't getting any! It'll probably be more like The Odd Couple." The sitcom failed to materialize however. In 2010, Drescher returned to television with her own daytime talk show, The Fran Drescher Tawk Show. While the program debuted to strong ratings, it ended its three-week test run to moderate success, resulting in its shelving. The following year, the sitcom Happily Divorced, created by Drescher and her ex-husband, Peter Marc Jacobson, was picked up by TV Land for a ten-episode order. It premiered there June 15, 2011. The show was renewed in July 2011 for a second season of 12 episodes, which aired in spring 2012. On May 1, 2012, TV Land extended the second season and picked up 12 additional episodes, taking the second season total to 24. The back-order of season two debuted later in 2012. Happily Divorced was cancelled in August 2013.  To promote Happily Divorced, Drescher performed the weddings of three gay couples in New York City using the minister's license she received from the Universal Life Church. Drescher hand-picked the three couples, all of whom were entrants into "Fran Drescher's 'Love Is Love' Gay Marriage Contest" on Facebook, based on the stories the couples submitted about how they met, why their relationship illustrated that "love is love" and why they wanted to be married by her.

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