Among other jobs, Romijn modeled for the swimsuit issue of Sports Illustrated and for Victoria's Secret. She also was the host of MTV's House of Style from 1998 to 2000. Rebecca is a fixture on annual lists of the world's most beautiful women by publications such as Maxim (2003-2007), AskMen.com (2001-,2003, 2005-2006) and FHM (2000-2005). She also appeared as a guest in the animated talk show Space Ghost Coast to Coast in an episode titled "Chinatown."

In 2000's X-Men, Romijn had her first major movie role as "Mystique"; she returned to the role in 2003's sequel X2: X-Men United, and again for X-Men: The Last Stand (2006). In these movies her costume consisted of blue makeup and some strategically placed prosthetics on her otherwise nude body. In X2: X-Men United she shows up in a bar in one scene in her "normal" look, and also in X-Men: The Last Stand, she appears as a dark-haired "de-powered" Mystique. She had her first leading role in Brian De Palma's Femme Fatale (2002).