In her early career in New York, Wagner "played several ensemble parts in the 1971 production of Lenny [the play], and her first marriage, to the set designer Robin Wagner, brought her into the industry’s A-list circles; she was at Robin’s side when the Director Michael Bennett shared ideas for A Chorus Line".

Wagner was a talent agent at Creative Artists Agency in Los Angeles, spending 15 years representing some of the top Hollywood actors, including Tom Cruise, Sean Penn, Oliver Stone, Val Kilmer, Demi Moore, Liam Neeson, Robert Towne, and Kathryn Bigelow. In 1993, she launched Cruise/Wagner Productions (C/W) with her former CAA client Tom Cruise. For the next 13 years, Cruise and she produced a wide range of films that earned numerous awards, widespread critical praise, and global box office success. The first film released under the C/W banner was the international hit Mission: Impossible, the success of which brought the company the 1997 Nova Award for Most Promising Producers in Theatrical Motion Pictures.

Wagner was honored by Premiere magazine with the Women in Hollywood Icon Award in 2001. The following year she was featured in Bravo's Women on Top, a documentary which profiled exceptional women in entertainment.

In 2004, Cruise and she were honored by Daily Variety as Billion-Dollar Producers. That same year, Wagner and Cruise received the UCLA/Producers Guild of America Vision Award.

In 2006, Wagner received the Sherry Lansing Award from the Big Brothers Big Sisters of America.

In 2008, Wagner was honored by the Costume Designers Guild with its Swarovski President's Award, and in 2011, she earned the Chicago International Film Festival’s Renaissance Award.

In 2012, Wagner executive produced Tony-nominated The Heiress and in 2014, Mothers and Sons, nominated for best new play.

Wagner serves on the Board of the National Film Preservation Foundation through the Library of Congress, Film Forum in New York and Carnegie Mellon University (lifetime member), where she received her degree and is an adjunct faculty member in the Master in Entertainment Industry Management program through the Heinz College. Wagner is a member of the American Cinematheque's Board of Directors and the Executive Committee of the UCLA’s School of Theater, Film and Television. Wagner will teach a course at UCLA School of Theater, Film and Television titled “Stage to Screen”. She is also an adjunct professor at Loyola Marymount University’s School of Film and Television (Practical Realities of Film Industry).