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Born to actors Bruce Dern and Diane Ladd, Dern embarked on an acting career in the 1980s and rose to prominence for her performances in Peter Bogdanovich's Mask (1985) and in David Lynch's films Blue Velvet (1986) and Wild at Heart (1990). She received a nomination for the Academy Award for Best Actress for her role as the orphan Rose in the drama film Rambling Rose (1991), and received her first Golden Globe for her performance in the television film Afterburn (1992). She achieved international recognition for her role as Ellie Sattler in Steven Spielberg's adventure film Jurassic Park (1993), a role she reprised in the sequels Jurassic Park III (2001) and Jurassic World Dominion (2022).

After winning two Golden Globes for her performances as Katherine Harris in the television film Recount (2008), and Amy Jellicoe in the comedy series Enlightened (2011–2013), Dern garnered her second Academy Award nomination for her performance as the mother of Cheryl Strayed in the biopic Wild (2014). She portrayed Renata Klein in the drama series Big Little Lies, winning a Primetime Emmy Award and a Golden Globe, and reunited with Lynch for Inland Empire (2006) and Twin Peaks: The Return (2017). She had supporting roles in the films Star Wars: The Last Jedi (2017), Little Women (2019), and Marriage Story (2019). Her performance as a divorce lawyer in Marriage Story won her the Academy Award for Best Supporting Actress, along with the corresponding BAFTA Award and Golden Globe.