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She first came to fame on Broadway as the singing and dancing ingenue in the original production of No, No, Nanette. From this, Munson had a very successful stage and radio career in 1930s in New York. She introduced the song "You`re the Cream in My Coffee" in the 1927 Broadway musical Hold Everything.

Ona Munson`s first starring role was in a Warner Brothers talkie called Going Wild (1930). Originally this film was intended as musical but all the numbers were removed prior to release due to the public`s distaste for musicals which had virtually saturated the cinema in 1929-1930. Ona Munson appeared the next year in a musical comedy called Hot Heiress in which she sings several songs along with her co-star Ben Lyon. She also starred in Broadminded (1931) and Five Star Final (1931). She briefly retired from the screen, only to return in 1938.

When David O. Selznick sought out the cast for his production Gone with the Wind, he first announced Mae West was to play Belle, but this was a publicity stunt. Tallulah Bankhead refused the role as too small. Munson herself was the antithesis of the voluptuous Belle: tall, freckled, and of slight build. But her skills as an actress electrified her screen test: it was all in the voice. She spoke deep and throaty in her test, and her voice conveyed sexiness and worldliness. The needed look for Belle could be created in the wardrobe and makeup departments.

Ona Munson’s career was stalemated by the acclaim of GWTW; for the remainder of her career, she was typecast in similar roles. Two years later, she played a huge role as another madam, albeit a Chinese one, in Josef von Sternberg`s film noir The Shanghai Gesture, a part that seemed written for Anna May Wong.

Munson was married three times, to actor and director Edward Buzzell in 1927, to Stewart McDonald in 1941, and designer Eugene Berman in 1949.

In 1955, plagued by ill health, she committed suicide at the age of 51 with an overdose of barbiturates in her apartment in New York.