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Get Him to the Greek (2010) and Bridesmaids (2011) established her as a comedic actress, and she has since appeared in several successful films, such as X-Men: First Class (2011), Neighbors (2014), Spy (2015), and X-Men: Apocalypse (2016).
Other films include the first two Insidious films (2010–2013), I Give It a Year, The Internship (both 2013), Annie (2014), Instant Family and Peter Rabbit (both 2018).
Her family was described by The Telegraph as "close-knit", and frequently kept her feet grounded as her career took off.
"At one point one of my sisters had a word with me saying, 'Watch yourself'", she once remarked.
A role in the award-winning film My Mother Frank (2000) was followed by her first leading role in Clara Law's The Goddess of 1967 (also 2000), which gained her the Volpi Cup for Best Actress at the 57th Venice International Film Festival.
Byrne revealed in a post-award interview that, prior to winning the Venice Film Festival Award, she was surprised by her own performance and found it confronting watching the film because her acting was "too depressing".
She is the youngest of their four children; she has an older brother, George, and two older sisters, Alice and Lucy.
In a 2009 interview, Byrne stated that her mother is an atheist, while both she and her father are agnostics.
Byrne appeared as Ellen Parsons in all fifty-nine episodes of the criminal thriller series Damages (2007–2010), which earned her two Golden Globe Awards and two Primetime Emmy Award nominations.Just being a jobbing actor trying to figure out life after high school".Throughout the 1990s, she appeared in several Australian television shows, such as Wildside (1997) and Echo Point (1995), and starred as an alterna-girl love interest in the film Two Hands (1999), opposite fellow up-and-coming actor Heath Ledger.In 2005, she also starred with Snoop Dogg in The Tenants, based on Bernard Malamud's novel.In 2006, Byrne portrayed Gabrielle de Polastron, duchesse de Polignac, a French aristocrat and friend of Marie Antoinette, in Sofia Coppola's Marie Antoinette, with Kirsten Dunst, and appeared, as a medical examiner who thinks the dead woman she is prepping is her missing sister, in the critically acclaimed thriller The Dead Girl, alongside Cillian Murphy and Chris Evans, and also an army medical officer in Juan Carlos Fresnadillo's 28 Weeks Later, the sequel to Boyle's 28 Days Later.