Stone left Elite and signed with IMG Models worldwide in 2006. In January she made her catwalk debut when Riccardo Tisci put her in his Givenchy couture shows in Paris. Later that year she was an exclusive for Calvin Klein. 2007 proved to be more lucky when she had a big Bardot-like spread in March’s Vogue Paris, and then got the cover for their April issue. "Sometimes a girl just touches you," Carine Roitfeld, the magazine’s Editor, said. The New York Times' fashion critic Cathy Horyn named her the "anti-model" in her On the Runway blog; describing her as not your typical catwalk android with her gapped front teeth, stunned expression, and Lurch walk, which can be attributed to her small size 7 feet – catwalk shoes are at least a size larger. All the buzz over Stone prompted New York Magazine to rank her No. 2 on their "Top Ten Models to Watch" for in New York Fashion Week.

Her spring/summer 2008 campaigns included Givenchy, Belstaff, Just Cavalli, and H&M. Her campaigns for autumn/winter 08 included CK, Givenchy, Belstaff, Hugo Boss Orange, Calvin Klein Cosmetics, and Jil Sander. Stone was one of the Models chosen to be in one of the fourteen covers of V magazine September 2008 issue. Shot by Inez van Lamsweerde and Vinoodh Matadin, each cover boasts a head shot of a famous model, either from the new crop of leading ladies or the supermodel era.

In the December 2009 issue of Vogue UK, Stone admitted undergoing inpatient rehabilitation for alcoholism earlier in the year.

Stone began dating English Comedian David Walliams in September 2009. They announced their engagement in January 2010. They were married at London's Claridge's hotel on 16 May 2010. In November 2012, the couple announced that Stone was pregnant with their first child, due mid-2013. On 6 May 2013, Stone gave birth to a baby boy, Alfred. It was reported on 4 March 2015 that, following five years of marriage, the pair had decided to try a trial separation, after 'drifting apart'. On 9 September 2015, Walliams filed for divorce from Stone, citing "unreasonable behaviour". The couple were granted a decree nisi the next day, dissolving the marriage six weeks after the date of filing.

Stone was featured in the 2011 Pirelli Calendar photographed by Karl Lagerfeld. Stone is part of history, in what marks Vogue UK's first multi-cover in the publication's 95-years, landing one of the three May 2011 covers in celebration of the Wedding of Prince william of Wales and Kate Middleton. She debuted on Forbes' World's Top-Earning Models list, ranking No. 7, with estimated earnings of $4.5 million since May of last year (2010–2011).

Stone was again featured in the 2012 Pirelli Calendar photographed by Mario Sorrenti and also as the face of Calvin Klein's 2012 Underwear campaign.

In March 2014, Stone again appeared on the cover of Vogue Paris and in April, American Harper's Bazaar.

In March 2015, Stone appeared on one of three Vogue Paris covers alongside Kate Moss and Daria Werbowy. Stone was also on the August cover of British Vogue, shot by Mario Testino.

Stone starred with Yvan Attal, Mathilde Bisson, Arthur Igual and Akaji Maro in the short film En Moi (In Me) directed by Laetitia Casta. The movie was selected for the closing ceremony of the 2016 Cannes Film Festival Critic's Week.