Mitchell's first novel, Ghostwritten (1999), moves around the globe, from Okinawa to Mongolia to pre-Millennial New York City, as nine narrators tell stories that interlock and intersect. The novel won the John Llewellyn Rhys Prize (for best work of British literature written by an author under 35) and was shortlisted for the Guardian First Book Award. His two subsequent novels, number9dream (2001) and Cloud Atlas (2004), were both shortlisted for the Man Booker Prize. In 2003, he was selected as one of Granta's Best of Young British Novelists. In 2007, Mitchell was listed among Time magazine's 100 Most Influential People in The World. Mitchell's American editor at Random House is novelist David Ebershoff.
In 2012 his novel Cloud Atlas was made into a film. In recent years he has also written opera libretti. Wake, based on the 2000 Enschede fireworks disaster and with music by Klaas de Vries, was performed by the Dutch National Reisopera in 2010. He has also finished another opera, Sunken Garden, with the Dutch composer Michel van der Aa, to be premiered in 2013 by the English National Opera.
Mitchell's sixth novel, The Bone Clocks, has 'dollops of the fantastic in it', and is about 'stuff between life and death'. It is not, as previously suggested, about a young girl growing up in Ireland. The opera Sunken Garden works as a prologue to David's forthcoming book, which will be finished in the second half of 2013. It will take place in the years between 1984 and 2057.