Named after her Grandfather "Cy" and Father "Bill", at age sixteen Cybill Shepherd won the 1966 "Miss Teenage Memphis" contest that landed her modelling work through high school and after. She quickly made a name for herself as a curvy 'real woman', which was a departure from the trend at the time of Twiggy-type waifs. This led to regular work as a magazine cover girl, and it was a 1970 Glamour magazine cover that caught the eye of film director Peter Bogdanovich. Upon seeing the cover in a supermarket check-out line, Bodganovich was reported to say "That's Jacy" referring to the role he was casting - and ultimately offered to Shepherd - in The Last Picture Show (1971). Her role as the teenage sexual ingenue would prove to be one of the most explosive and promising debuts of any film actress.

During the filming, the then 20-year-old was required to film a nude scene in a pool. Still photos obtained from that nude scene appeared in Playboy magazine without Shepherd's consent. She sued and won, setting a precedent regarding public figures. Also during the filming of The Last Picture Show, Shepherd began an affair with Bogdanovich that would last off and on for eight years. Shepherd also famously met Elvis Presley in 1972, and she mentions in her autobiography that they had a short, uneventful affair. Years later, in an interview with E! television, Shepherd spoke of the relationship with Presley, saying, "He was a wonderful lover, very sexy."

Soon, Cybill Shepherd was cast opposite Charles Grodin in The Heartbreak Kid (1972). She played Kelly, the beautiful, sunkissed young woman that Grodin's character falls for while on his honeymoon in Miami. Directed by Elaine May, it was a critical and box office hit, showing off comedic talents.

In 1974, Shepherd again teamed with Peter Bogdanovich for a starring role in Daisy Miller, based on the Henry James novella. The role - a period piece set in Europe - was a challenging one, especially for a relatively inexperienced Shepherd. It proved to be a box office failure. In a 1987 interview, Shepherd shared that she had recently viewed the film again, and said "It's frustrating to watch now because I've learned so much as an actor, and I would have approached that character so differently".

Shepherd bounced back with good reviews for her work in Martin Scorsese's Taxi Driver (1976), a role in which "she appeared like an angel, out of this filthy mass", in the words of Robert De Niro's character. According to Shepherd, Martin Scorsese had requested a "Cybill Shepherd type" for the role. She portrayed an ethereal beauty with whom De Niro's title character becomes enthralled.

After a series of less successful roles, including the remake of Hitchcock movie The Lady Vanishes, she left show business in 1978 and moved back to Memphis, saying she was fed up with Hollywood.

Back from Memphis, Shepherd won the role of Colleen Champion in the night-time drama The Yellow Rose (1983), opposite Sam Elliott. Although critically acclaimed, the series lasted only one season.

A year later, Cybill was cast as Maddie Hayes in ABC's Moonlighting (1985-1989), which became the role that would define her career. The producers knew that her role depended on having chemistry with her co-star, and she was involved in the selection of Bruce Willis. They quickly became one of the most celebrated television duos. A lighthearted combination of mystery and comedy, the series won Shepherd two Golden Globe awards.

She starred in Chances Are (1990) with Robert Downey Jr. and Ryan O'Neal, receiving excellent reviews. She then reprised her role as Jacy in Texasville (1991), the sequel to The Last Picture Show (1971), as the original cast (including director Peter Bogdanovich) reunited 20 years after filming the original. She also appeared in Woody Allen's Alice (1991), and Once Upon a Crime (1992), as well as several television movies.

In 1997, she won her third Golden Globe award, for CBS' Cybill (1995-1998), a television sitcom, in which the title character - Cybill Sheridan, an actress struggling with hammy parts in B movies and bad soaps - was loosely modeled on herself (including portrayals by actors of her two ex-husbands). As she had on Moonlighting, she was involved in casting another unknown co-star (Christine Baranski) who proved to be an asset to the show's popularity.

In 2000, Shepherd's autobiography was published, titled Cybill Disobedience: How I Survived Beauty Pageants, Elvis, Sex, Bruce Willis, Lies, Marriage, Motherhood, Hollywood, and the Irrepressible Urge to Say What I Think., written in collaboration with Aimee Lee Ball.

She has played Martha Stewart in two TV movies: Martha, Inc.: The Story of Martha Stewart (2003) and Martha: Behind Bars (2005).

In June 2006, it was announced that Shepherd has signed to star in 11 episodes of Showtime drama The L Word, in it's upcoming fourth season in 2007.