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Megan was born in Los Angles to Martha, a model, and Carter Mullally Jr, a contract player for Paramount. They soon moved to Oklahoma City, where Megan grew up. Growing up an only child, Megan became an accomplished singer and dancer, with a very active imagination. When Megan reached high school, she was a soloist with Oklahoma City's Ballet Company.

After graduating, Megan went on to Northwestern University intending to study English and Art History. Megan's singing, dancing and acting talents, however, could not long go unnoticed, and she was soon performing in student productions. Finding her passions lay in the performing arts, Megan dropped out of University to pursue an acting career.

Remaining in Chicago, Megan spent six years working in theater. She made her film debut in "Risky Business", opposite Tom Cruise, but her part was cut to merely a background extra. Megan was in various other films during the 80s, playing small parts and never quite getting the break her talents so obviously deserved. Megan spent the following years making guest appearances on numerous television shows from "Ned & Stacey" and "Caroline in the City" to "Seinfeld", "Mad About You" and "Frasier".

In 1994, Megan discovered Broadway, or Broadway discovered Megan. In 1995, Megan starred as Rosemary, in "How to Succeed in Business Without Really Trying", opposite Matthew Broderick, for which she received an Outer Critics Circle Award nomination. She also appeared as Marty in the revival of "Grease", starring Rosie O'Donnell (1994).

In 1998, Megan was offered the life changing role of Karen Waker, on NBC's "Will & Grace", and her career finally began to move in the direction in which she had been working for so long. Megan won various awards for her role as Karen Walker, including two Emmys (2000 and 2006) for Outstanding Supporting Actress in a Comedy Series. In addition, she has won 3 Screen Actors Guild Awards for Outstanding Performance by a Female Actor in a Comedy Series (2002-2004). Megan and Debra Messing were also honored in 2005 for the Lucy Award celebrating outstanding women in comedy and Megan has been nominated for 4 Golden Globe Awards for Best Performance by an Actress in a Supporting Role in a Series and was recognized from the Television Critics Association for Outstanding Individual Achievement in Comedy.

In September 2003, Megan's personal life changed as well, when she married her boyfriend of 2 years, Nick Offerman in a private ceremony at their Los Angeles home.

In 2006, Megan took a different approach in her career and took a shot at the crazy world of daytime television by starring in her own one-hour talk show, properly titled, "The Megan Mullally Show." Although the show did not last, the humor and diversity she brought to the show was heartwarming and enlightening. The show was cancelled in early January 2007.

Megan also has a band - The Supreme Music Program - with whom she has made three cds and performed countless times in the Los Angeles area.