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McDonald, 43, took home the statue for best lead actress in a play for her portrayal of a broken-down Billie Holiday in "Lady Day at Emerson's Bar and Grill."
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The play tells the "personal tales of difficult choices, bad breaks, worse men, and some of the most glorious songs ever written," according to the show's website, which calls McDonald's performance, "the role she was born to play."
After McDonald's big win, she tearfully accepted her award to a standing ovation and paid tribute to the legacy of female African-American singers. She also thanked her late parents for ignoring their doctor's advice to medicate their overactive daughter and instead directing her toward the theater.
McDonald has previously won awards for her roles in "Carousel," "Master Class," "Rag Time," "A Raisin In The Sun," and "Porgy and Bess."
Her historic win tops Angela Lansbury and Julie Harris's previous records of five acting Tonys each.