In 1930, movie producer and entrepreneur Howard Hughes became interested in Jean and cast her in Hell's Angels. In Hell's Angels, she spoke the now famous line, "Would you be shocked if I changed into something more comfortable?" Jean's appearance in Hell's Angels solidified her role as America's new sex symbol. This victory was followed by another hit, Platinum Blonde, and several films with Clark Gable. In total, she and Gable would star in six movies together including Red Dust, The Secret Six and Wife vs. Secretary. During the filming of Red Dust, Jean's second husband of only two months, producer Paul Bern, committed suicide.

In 1933's Dinner at Eight, Jean was at her comedic best. Later that year she starred in Bombshell, a Hollywood parody based loosely on her real-life experiences with her controlling mother and greedy stepfather. Also in 1933, Jean married cinematographer Harold Rosson in a union that would only last eight months. To accompany her escalating career, in 1935 she legally changed her name to Jean Harlow, her mother's maiden name.

Following the end of her marriage, Jean found the love of her life in actor William Powell. They were together for two years, however before they could wed, Jean's health declined. While filming Saratoga in 1937, Jean was hospitalized with uremic poisoning and kidney failure, a result of the scarlet fever she had suffered during childhood. In the days before dialysis and kidney transplants, nothing could be done and Jean died on June 7, 1937. The film had to be finished using long angle shots and a double, Mary Dees. Clark Gable was reported to have said that he felt as if he was "in the arms of a ghost." After a large Hollywood funeral organized by Louis B. Mayer of MGM, Jean was buried in the mausoleum in Forest Lawn Glendale, in Los Angeles.

Jean was labeled a "screen siren" for her sensational dialogue and revealing costumes, but audiences, directors and producers alike appreciated her flair for comedy and drama. Had she lived longer, it is likely that she would have stayed on a successful path in Hollywood for years to come. In an acting career that lasted only 10 years, Jean Harlow forever established herself as one of the most captivating actresses of all time.

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