Manchester was born in the Bronx, a borough of New York City, to a musical family. Her father was a bassoonist for the New York Metropolitan Opera.
Manchester started a singing career at an early age, learning the piano and harpsichord at the Manhattan School of Music and Arts, singing commercial jingles at age 15, and becoming a staff writer for Chappell Music while attending Manhattan's High School of Performing Arts.
She studied songwriting at New York University with Paul Simon. Manchester then appeared on the Manhattan club scene, where she was discovered by Barry Manilow and Bette Midler, who took her on as one of her backup singers, the Harlettes in 1971.
Her debut album, Home to Myself, was released in 1973; Manchester co-wrote many of its songs with Carole Bayer Sager. Two years later Manchester's album Melissa produced her first top ten hit, "Midnight Blue," which peaked at #6 on the Billboard charts.
Manchester collaborated with Kenny Loggins to co-write Loggins' 1978 hit duet with Stevie Nicks, "Whenever I Call You Friend." She would later record this herself for her 1979 Melissa Manchester album. At this time, she guest-starred on the CBS-TV daytime soap opera Search for Tomorrow to teach a main character, who was a singer-songwriter, the essentials of the craft.
In 1979 Manchester hit #10 on the charts with her version of Peter Allen's "Don't Cry Out Loud," for which she received a Grammy nomination for Best Pop Female Vocal Performance.
In 1979 she performed two nominated songs on the Academy Awards show, "The Promise," and "Through The Eyes of Love" (theme song from Ice Castles). The winning song that year was "It Goes Like It Goes," from Norma Rae.
In 1982 Melissa scored her biggest hit ever, "You Should Hear How She Talks About You," which won a Grammy for Best Female Vocal Performance and reached at #5 on the Billboard charts. Surprisingly it was her last Top 40 Pop hit, but Manchester continued to place singles on the Adult Contemporary charts throughout the 1980s.
Her last top 10 entry on the AC chart was a 1989 updating of Dionne Warwick's "Walk On By." The single was pulled from album "Tribute," which honored some of the singers that influenced her style.
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-----In spring 2004, Manchester returned with her first album in 10 years: When I Look Down That Road. She played herself on a two-day guest appearance on the ABC-TV daytime soap General Hospital, to sing the song for Robin Scorpio and her AIDS-afflicted boyfriend Stone Cates.
Through the 1980s and 1990s Manchester alternated recording with acting, appearing with Bette Midler in the film For the Boys, on the television series Blossom, and co-writing and starring in the musical I Sent A Letter To My Love based on the Bernice Rubens novel of the same name.
In April 2007, Manchester returned to theater, starring in the Chicago production of HATS! The Musical, a show to which she had, with Sharon Vaughn, contributed two songs.
Also in 2007, she recorded a duet with Barry Manilow on a cover of the Carole King classic "You've Got A Friend" on Manilow's The Greatest Songs of the Seventies.
In 2008 she released a new single, "The Power of Ribbons," to digital retailers. Proceeds of the single benefit breast cancer research.