At 18, Roitfeld began modeling, having been scouted on a street in Paris by a British photographer's assistant. She became a writer and then a stylist for French Elle.
Roitfeld went on to work as a consultant for and muse to Tom Ford at Gucci and Yves Saint-Laurent for six years and also contributed to the images of Missoni, Versace, and Calvin Klein.
She was approached by Condé Nast's International Chairman Jonathan Newhouse to edit Vogue Paris in 2001. In April 2006, there were rumors that Roitfeld was being approached by the Hearst Corporation to take over Glenda Bailey's editor-in-chief position at U.S. Harper's Bazaar.
In January 2010, she was named in Tatler magazine’s top-10 best-dressed list. She was listed as one of the fifty best-dressed over 50s by the Guardian in March 2013.
On December 17, 2010, Roitfeld resigned after ten years at Vogue Paris to concentrate on personal projects. She left the magazine at the end of January 2011. Speculation that she would be joining Tom Ford at his namesake company were refuted by Ford. She was succeeded at Vogue Paris on February 1, 2011, by Emmanuelle Alt, who had served as fashion director under Roitfeld.
At the end of 2011 she confirmed the rumors that she is working on her own magazine with a different approach than the one at Vogue Paris, saying, "I will always be irreverent in my own way, but I will try to use new approaches. I've used a lot of cigarettes, a lot of sexy pictures, a lot of naked girls. I will try to do something totally different now, because I don't want to get bored of myself or to bore my readers. So, if I learn something new today, I will use it. I have to reinvent myself".