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Lynch had a recurring role in the CBS sitcom Two and a Half Men (2004–2014), for which she received a nomination for a Primetime Emmy Award, as well as recurring roles in the Showtime drama series The L Word (2005–2009), the CBS police drama series Criminal Minds (2006–2020), the CBS All Access drama series The Good Fight (2017–present), and the Amazon Prime Video period comedy series The Marvelous Mrs. Maisel (2017–present), for which she received a Primetime Emmy Award. Since 2013, she has hosted the NBC game show Hollywood Game Night, which has earned her two Primetime Emmy Awards.

Lynch has had roles in numerous mainstream comedy films, such as The 40-Year-Old Virgin (2005), Talladega Nights: The Ballad of Ricky Bobby (2006), Role Models (2008), Paul (2011), and The Three Stooges (2012). She has lent her voice to numerous animated films, including Space Chimps (2008), Ice Age: Dawn of the Dinosaurs (2009), Shrek Forever After (2010), Rio (2011), Wreck-It Ralph (2012), and Ralph Breaks the Internet (2018).

In 2013, Lynch received the 2,505th star on the Hollywood Walk of Fame in the television category, located at 6640 Hollywood Blvd. Among her numerous accolades, Lynch has received five Primetime Emmy Awards, two Screen Actors Guild Awards, and a Golden Globe Award.