Lyonne started her career as a child actress, making her first uncredited appearance in Heartburn (1986), recurring in Pee-wee's Playhouse (1986), and supporting in Dennis the Menace (1993). She transitioned to taking on teen roles in several independent films such as Everyone Says I Love You (1996), Slums of Beverly Hills (1998), But I'm a Cheerleader (1999), and Party Monster (2003) as well as in broad comedic films such as American Pie (1999), American Pie 2 (2001), Scary Movie 2 (2001), and American Reunion (2012).
She found a career resurgence and Emmy Award nominations for her performances as Nicky Nichols on the Netflix comedy-drama series Orange Is the New Black (2013–2019), a software engineer stuck in a time loop in the Netflix's comedy-drama series Russian Doll (2019–2022), and a woman who can tell when people are lying in the Peacock crime comedy series Poker Face (2023–present), the former of which she also served as a co-creator, writer, director, and executive producer of the series. She also starred in the Netflix drama film His Three Daughters (2024).
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