Lysette was born in Lexington, Kentucky, and grew up in and around Dayton, Ohio.
In her late teens, she was a track athlete[citation needed] and performed as a showgirl in bars and clubs in Dayton and Columbus, Ohio. She moved to New York City after high school in search of opportunities. Lysette was estranged from her biological family and struggled financially due to her gender transition which led her to find acceptance in the underground New York ball culture scene, of which she has been a member since young adulthood. She began her actor training in New York City, studying at various acting studios in 2007. Her television debut was a guest appearance as Lila in an episode of Law & Order: Special Victims Unit in 2013, making her one of the first trans people to appear in a cisgender speaking role on primetime television in the US.
After working in non-transgender roles, Lysette came out publicly as trans through her role as Shea on the Amazon series Transparent, which debuted in 2014. On the show, she plays a transgender yoga teacher and friend of Maura Pfefferman (Jeffrey Tambor). Lysette originally auditioned for the role of Davina. The third season of Transparent contains a storyline in which Shea has a romantic relationship with a cisgender heterosexual man, which has been called "a groundbreaking TV moment for a trans character." Lysette was an unpaid consultant for the 2015 film The Danish Girl.

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