In 1999, at the age of 16, she appeared in the Victoria's Secret lingerie catalogue. The shoot caused controversy, as Victoria's Secret stated that they would not use models younger than 18. Soon after the Victoria's Secret shoot, she was signed by Versace, Ralph Lauren and Valentino.
Since 1999 she has modeled for Sports Illustrated Swimsuit Issue, Marie Claire, ELLE, Vogue, Harper's Bazaar, Numéro, i-D, Arena and many others.
Fontana has been the face of a variety of advertising campaigns including Shiatzy Chen, Armani Jeans, Chanel, Bulgari, Colcci, Disritmia, Dolce and Gabbana, Emporio Armani, Enrique Martinez, Escada, H&M, Helena Rubinstein, Hugo Boss, Hussein Chalayan, Leonisa, Massimo Dutti, Mango M. Officer, Nicole Farhi, Oscar de la Renta, Peter Hahn, Philips, Ralph Lauren, Revlon, Roberto Cavalli, Rosa Chá, Saks Fifth Avenue, Tommy Hilfiger, Triton, Valentino, Versace, Victoria's Secret, Vivara and others. Photographed by Steven Meisel, she was presented on the September 2004 cover of American Vogue as one of the "Models of the Moment".
Fontana can be seen in the Spring/Summer 2011 campaigns for Escada, Dolce and Gabbana, Uniqlo & Ann Taylor.
Fontana is the face of Viktor & Rolf's fragrance Flowerbomb as of 2014 as well as Bvlgari's Goldea from 2015.
In 2008, Fontana made her debut on the Forbes The World's 15 Top-Earning Models list at place 11, having earned $3 million.
She has appeared in the Pirelli Calendar on a number of occasions, including in the 2011 calendar, which features models posing as Greek and Roman gods, photographed by Karl Lagerfeld.