Wood successfully made the transition from child star to ingenue at age 16 when she co-starred in Nicholas Ray's Rebel Without a Cause with James Dean and Sal Mineo. Her performance won her an Oscar nomination for Best Supporting Actress. She followed this with a small but crucial role in John Ford's The Searchers opposite John Wayne. Her sister, Lana played her as a child in the film's earlier scenes. She graduated from Van Nuys High School in 1955.

Signed to Warner Brothers, Wood was kept busy during the remainder of the 1950's in many 'girlfriend' roles that she found unsatisfying. The studio cast her in two films opposite Tab Hunter, hoping to turn the duo into a box office draw that never eventuated. Among the other films made at this time were Kings Go Forth with Frank Sinatra and the title role in Marjorie Morningstar.

After appearing in the box office flop, All the Fine Young Cannibals with then husband, Robert Wagner, Wood's career was salvaged by her casting