Heatherton was born and raised in Skokie, Illinois, the daughter of Laura (née Stein) and Mark Bubley. Her family is Jewish, and she attended Solomon Schechter Day School, a Jewish day school, as well as Niles North High School.
Heatherton was discovered by modelling scout Arri Taylor while vacationing with a friend on South Beach, Miami. At the age of 17 Heatherton moved to New York City and signed with the Marilyn Agency. In September 2006 she launched her career in New York City, walking for Diane von Fürstenberg. She has since walked for Prada, Stella McCartney, Chanel, Tommy Hilfiger, Marc Jacobs, Jason Wu, Carolina Herrera, Michael Kors, Christian Lacroix, Lacoste, Valentino, Oscar de la Renta, Zac Posen, Dolce & Gabbana, Moschino, L.A.M.B., Elie Saab, Carmen Marc Valvo, Derek Lam, Etro, Isaac Mizrahi, and others.
At the age of 17, she booked her first cover with Italian Flair. She has since appeared on the covers of D, Grazia, Velvet, Elle Czech, Elle Russia, Elle France, Elle Serbia, GQ Spain, GQ Germany, Beauty in Vogue, Rush, Flair Austria, and Muse. She also appeared on the cover of British GQ, GQ Mexico, GQ Russia, GQ Romania, and GQ China alongside fellow Victoria's Secret Angels Candice Swanepoel, Lindsay Ellingson, and Lily Aldridge. Additionally, she has appeared in editorials for Mixte, British Elle, Interview, Italian D, Numero, V, Italian Marie Claire, and Harper's Bazaar.
Heatherton's campaigns include Chopard, XOXO, Diesel, Versace, Lord & Taylor, Blanco, BLK DNM, John Galliano, H&M, Blugirl, Lacoste, Armani, Liu-Jo, Valentino, Karl Lagerfeld, Osiris, Pronovias, and Dolce & Gabbana.
Heatherton is a featured supermodel on the Victoria's Secret website. She began walking in the Victoria's Secret Fashion Show in 2008. In 2010, Heatherton was officially contracted as a Victoria's Secret Angel. Heatherton has appeared on several television ads for the brand, and has been a featured face for many of the brands campaigns, including a sole featuring billboard in New York City for the company's Showstopper launch. She has appeared at many of the brand's press tours and store events.
In September 2007 Heatherton was named one of the best new girls of the season by Elle.com, selected by casting director Douglas Perrett. That same month she was also named one of the season's up-and-comers by WWD.
As of December 2013 Heatherton is ranked No. 15 on Models.com top 25 sexiest models list.
In 2013 it was announced that Heatherton left Marilyn agency to sign with IMG.