After working in theatre in Chicago, Mullally moved to Los Angeles in 1985 and began to appear in supporting roles in film and television productions. She made her Broadway debut in Grease in 1994 and she has since appeared in several Broadway musicals. From 1998 until 2006, she played Karen Walker on the TV sitcom Will & Grace. From 2006 until early 2007, Mullally hosted the short-lived talk show The Megan Mullally Show. She has since appeared in guest-starring roles in television programs such as Parks and Recreation, Happy Endings, 30 Rock, Up All Night, Boston Legal, and a GLAAD Award-winning episode of The New Adventures of Old Christine. In 2010, Mullally starred as Lydia in the second season of Party Down. She also co-stars as Chief on Adult Swim's Childrens Hospital, and has recurred as Tammy Swanson on NBC's Parks and Recreation, Dana Hartz on ABC's Happy Endings, and Aunt Gayle on the FOX animated comedy Bob's Burgers.
She received seven consecutive Emmy Award nominations for "Outstanding Supporting Actress in a Comedy Series" for her role on Will & Grace, winning twice in 2000 and 2006. She has also received four Screen Actors Guild Awards for her performance, and was nominated for four Golden Globe awards.
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