Born in London and brought up in Berkshire, Clarke first gained an interest in acting as a child after seeing the musical Show Boat, on which her father was working as a sound engineer. She was educated at Rye St Antony School, Headington and graduated from secondary school at St. Edward's in Oxford, where she appeared in two plays, before studying at the Drama Centre London, where she graduated from in 2009, and appeared in ten different stage productions. Some of her earliest work following graduation included a role in a play by the Company of Angels, two commercials for Samaritans, and a University of London students' short film. Her television debut came with a guest appearance in an episode of the British soap opera Doctors and she was named as one of the UK Stars of Tomorrow by Screen International magazine for her role in Syfy's film Triassic Attack (2010).

Clarke rose to prominence in 2011 for her breakthrough role as Daenerys Targaryen in the HBO series Game of Thrones, a performance that has gained her both critical and popular acclaim. She has been nominated for three Primetime Emmy Awards for Outstanding Supporting Actress in a Drama Series (2013, 2015-2016), four Screen Actors Guild Awards (2012, 2014-2016), and two Critics Choice Television Awards for Best Supporting Actress in a Drama Series (2013, 2016), among other numerous accolades.

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