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Applegate appeared in the 40th season of Sesame Street, explaining the word "booth" with Elmo in a Word of the Day segment, and in the first DVD release of the new Shalom Sesame, "Welcome to Israel" (2010).
She starred in the ABC sitcom Samantha Who?, and on Broadway in Sweet Charity. Her film appearances include Tim Burton's Mars Attacks! and Don't Tell Mom the Babysitter's Dead. Other television credits include King of the Hill, Friends, and Still the Beaver.