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After early breakthroughs in Mystic Pizza (1988) and Steel Magnolias (1989), Roberts solidified her status as a leading lady with the romantic comedies Pretty Woman (1990), My Best Friend's Wedding (1997), Notting Hill (1999), and Runaway Bride (1999). Roberts won the Academy Award for Best Actress for her portrayal of the title role in the biographical drama Erin Brockovich (2000). She then starred in films such as Ocean's Eleven (2001), Ocean's Twelve (2004), Charlie Wilson's War (2007), Valentine's Day (2010), Eat Pray Love (2010), August: Osage County (2013), Wonder (2017), Ticket to Paradise (2022), Leave the World Behind (2023), and After the Hunt (2025). On television, she starred as a physician during the AIDS crisis in the HBO film The Normal Heart (2014), for which she earned a Primetime Emmy Award nomination, a social worker in the first season of the streaming series Homecoming (2018), and portrayed Martha Mitchell in the Starz political limited series Gaslit (2022).

Roberts runs the production company Red Om Films, through which she has served as an executive producer for various projects she has starred in, as well as for the first four films of the American Girl franchise (2004–2008). She has served as the global ambassador for Lancôme since 2009. She was the world's highest-paid actress for most of the 1990s and the first half of the 2000s. People magazine has named her the most beautiful woman in the world a record five times.