Her first break was a bit part in the movie Saturday Night Fever (1977).
Drescher's voice is a combination of a high nasal pitch and a Queens, New York accent that people find either annoying, endearing, or humorous (or all three). In her autobiography, Drescher discusses the fact that this is her real voice — even though it is played up a little on-camera — and discusses the many voice lessons she had to take to overcome it for movie auditions, only to have it, and her machine-gun titter, end up being her trademark. Her first book is appropriately and humorously titled Enter Whining.
Fran has also appeared in a number of films, including This Is Spinal Tap (1984), UHF (1989) starring "Weird Al" Yankovic, Jack (1996), directed by Francis Ford Coppola, The Beautician and the Beast (1997) (for which she was also executive producer) and Picking Up the Pieces (2000) co-starring Woody Allen. In 2007 Fran announced she would voice the character of Pearl in the animated movie Shark Bait.
Drescher married her highschool sweetheart, Peter Marc Jacobson, in 1978. Jacobson was Drescher's constant supporter in her show-business career, and he wrote, directed, and produced her signature television series, The Nanny. They divorced in 1999.
In January 1985, robbers ransacked Drescher's and Jacobson's Los Angeles apartment and raped her and a friend at gunpoint. It took her many years to overcome this ordeal, and it took her even longer to admit this to the press. She was paraphrased as saying in an interview with Larry King that although it was a traumatic experience, she found ways to turn it into something positive. In her book Cancer Schmancer, the actress writes: "My whole life has been about changing negatives into positives." She saw her rapist sent to prison.
After separating in 1996, Fran (who never had children) divorced her husband, Peter Marc Jacobson, in 1999. She then dated a man sixteen years her junior from 1998–2002. Her beloved dog, Chester, who made many appearances in her movies and on The Nanny, died in 2000 at age eighteen. She now has a chocolate Pomeranian named Esther and lives in New York.
Drescher was admitted to Los Angeles's Cedars Sinai Hospital on June 21, 2000, after doctors diagnosed her with uterine cancer. But emergency surgery caught it early as it was only at Stage 1 and she didn't have to undergo chemotherapy. She has been given a clean bill of health and no post-operative treatment has been ordered. She wrote about her experiences in her second book, Cancer Schmancer.
Fran says "we need to take control of our bodies, become greater partners with our physicians and galvanize as one to let our legislators know that the collective female vote is louder and more powerful than that of the richest corporate lobbyists." Her goal is to live in a time when women's mortality rates drop as their healthcare improves and early cancer detection increases. More information can be found on her website at cancerschmancer.org
In 2003, Drescher appeared in episodes of the short lived sitcom, Good Morning, Miami as Roberta Diaz.
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 . In the same year, she also gave her voice to the role of the 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. The program was cancelled after eight episodes.
On February 23, 2008, on Rosie O'Donnell's video blog it was announced that Rosie and Fran would be doing a "fun, happy, family comedy" together. It is said to be called 'The New 30'.
On February 29, 2008, Fran went on Larry King Live to discuss the Obama/Clinton primary.
On June 17, 2008, Fran went on "Chelsea Lately" and discussed many different topics.