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Theron came to international prominence in the 1990s by playing the leading lady in the Hollywood films The Devil's Advocate (1997), Mighty Joe Young (1998), and The Cider House Rules (1999). She received critical acclaim for her portrayal of serial killer Aileen Wuornos in Monster (2003), for which she won the Silver Bear and Academy Award for Best Actress, becoming the first South African to win an acting Oscar. She was nominated twice more for the Oscar for portraying a sexually abused woman seeking justice in the drama North Country (2005) and Megyn Kelly in the biographical drama Bombshell (2019). She received praise for playing troubled women in Jason Reitman's comedy-dramas Young Adult (2011) and Tully (2018).

Theron has starred in several commercially successful action films, including The Italian Job (2003), Hancock (2008), Prometheus (2012), Mad Max: Fury Road (2015), Atomic Blonde (2017), and The Old Guard (2020), as well as several Fast & Furious installments: The Fate of the Furious (2017), F9 (2021), and Fast X (2023). On television, she earned a nomination for the Primetime Emmy Award for her portrayal of Britt Ekland in the biographical film The Life and Death of Peter Sellers (2004).

Since the early 2000s, Theron has ventured into film production with her company Denver and Delilah Productions. She has produced numerous films, many in which she had a starring role, including The Burning Plain (2008), Dark Places (2015), and Long Shot (2019). Theron became an American citizen in 2007, while retaining her South African citizenship. In 2016, Time named her one of the 100 most influential people in the world.