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At age 15, she was diagnosed with leukemia. Bayer stated that while battling the disease, she discovered the meaning of comic relief. “I don’t know if it made me funnier, but it was so amazing, how it made everything be O.K.,” she said.

In 2019, Bayer played Mia Cooper, the ex-wife of Taran Killam's character, in a recurring role on ABC's Single Parents. Starting in 2018 Bayer has played Amy, a former baker who loses her job because of Karen and subsequently works for Karen's baseball team, in a recurring role on NBC's Will & Grace.

In June 2019, she published the children's book How Do You Care for a Very Sick Bear?, which teaches children how to support friends with long-term illnesses.

Bayer suffered from leukemia as a teenager. The Make-A-Wish Foundation granted her wish to send her family on vacation to Hawaii. In gratitude and recognition, Bayer is involved with the foundation. In 2015, she hosted the foundation's Evening of Wishes Dinner to help raise funds for wishes for children with life-threatening illnesses.

As of 2012, Bayer was collaborating with her brother Jonah on the web series Sound Advice for Above Average. Bayer stars as Janessa Slater, a media coach who helps famous musicians change their image.

Bayer joined the cast of Saturday Night Live as a featured player on September 25, 2010. Beginning with the 2012–2013 season, Bayer was promoted to repertory status. She has been praised for her performance on the show, with HitFix calling her "one of the strongest members of the ensemble" and Rolling Stone calling her "Saturday Night Live's secret weapon". In 2014, she was nominated for an American Comedy Award for her work on the show., and in 2017 she was nominated for a Primetime Emmy Award for Outstanding Supporting Actress in a Comedy Series. Bayer departed SNL on May 20, 2017 after seven years on the show. At the time of her departure, she was the show's all-time longest-serving female cast member with 149 episodes, but has since been surpassed by Kate McKinnon.

Bayer graduated from Orange High School in 2000 and attended the University of Pennsylvania, where she majored in communication and French, graduating in 2004.

Vanessa Polster Bayer (born November 14, 1981) is an American actress and comedian. She is best known for being a cast member on Saturday Night Live from 2010 to 2017, which earned her an Emmy nomination. Bayer also appeared in films such as Trainwreck (2015), Office Christmas Party (2016), Carrie Pilby (2016), and Ibiza (2018).