While under contract to Warner Bros., Miles was cast alongside her future husband Gordon Scott in the 1955 film Tarzan's Hidden Jungle as Tarzan's love interest. The following year, she was cast by director John Ford as Jeffrey Hunter's love interest in the John Wayne Western The Searchers (1956), and appeared in the movies Wichita, directed by Jacques Tourneur and 23 Paces to Baker Street with Van Johnson. Also in 1956, Miles starred as Rose Balestrero, the fragile wife of Manny Balestrero, a musician falsely accused of a crime and played by Henry Fonda, in the film The Wrong Man. The movie was directed by Alfred Hitchcock, and is one of only a few Hitchcock films based on real-life events. Signing a five-year personal contract with Hitchcock in 1957, Miles was widely publicized as the director's potential successor to Grace Kelly. Two years prior, Hitchcock had directed Miles in the role of Ralph Meeker's emotionally troubled new bride in "Revenge", the pilot episode of his television series Alfred Hitchcock Presents.  Vertigo (1958), a project Hitchcock designed as a showcase for his new star, was met with production delays. Miles's subsequent pregnancy would cost her the lead role which eventually went to Kim Novak with whom Hitchcock reportedly clashed, although Ms. Novak has stated in interviews that she did not have trouble working with Hitchcock on the film. Vertigo (which also starred James Stewart) was not a financial or critical success at the time, with Hitchcock claiming that Novak was miscast. Despite Hitchcock's disappointment regarding Vertigo, he continued to work with Miles, eventually casting her in what is arguably the role for which she is most remembered, that of Lila Crane in Psycho. In the film, she portrayed the determined sister of the doomed motel guest Marion Crane (Janet Leigh), who teams up with Marion's boyfriend and a private investigator to find her. Miles later appeared in two episodes of The Alfred Hitchcock Hour (in 1962 and 1965). In 1962, Miles reunited with director John Ford for the film The Man Who Shot Liberty Valance. Starring alongside her former co-star from The Searchers, John Wayne, she is pursued by both Wayne and James Stewart, two very different men competing for her hand in marriage. In addition to her film appearances, Miles was featured in many popular television shows throughout her career, including Gunsmoke, Wagon Train, Laramie, The Twilight Zone and the western series Riverboat, starring Darren McGavin and Burt Reynolds. She also co-starred in the first episode of ABC's The Fugitive (titled "Fear in a Desert City"), as well as guest-starring in episodes of The Outer Limits, Burke's Law, The Eleventh Hour, The Man from U.N.C.L.E. and Ironside. In 1965, Miles had a supporting role in three episodes of the CBS series My Three Sons. The same year, she co-starred with lead actors Robert Culp and Bill Cosby in the pilot episode of the TV series I Spy entitled "Affair in T'Sien Cha" (although the pilot was not actually broadcast until midway through the series’ first season). Other notable films in which Miles appeared included the Walt Disney film Follow Me, Boys! (1966) with Fred MacMurray, and Hellfighters (1968), reuniting again with John Wayne. Miles had also filmed scenes with Wayne for the movie The Green Berets (also 1968), playing Wayne's character's wife. However, with Warner Bros. wanting more action in the film, her scenes were cut. Miles continued to appear in numerous TV films and TV series during the 1970s, including the pilot for the TV series Cannon (broadcast in March 1971) as the wife of a deceased war comrade of private investigator Frank Cannon, played by William Conrad. She guest-starred in a further two episodes of the series in different roles during its run. In 1973, she appeared alongside Peter Falk in "Lovely But Lethal", an episode of NBC's Columbo, playing a cosmetics queen who commits murder. She also made guest appearances in episodes of Hawaii Five-O, The Streets of San Francisco, and Fantasy Island among others. In 1983, more than 20 years after Psycho, Miles reprised the role of Lila Crane in Psycho II, joining Anthony Perkins in the sequel. Miles and Perkins were the only stars of the original film to appear in this second installment. Miles continued to appear in a number of TV and film productions during the 1980s, with appearances in the movies The Initiation (1984) and Into the Night (1985), and guest-starring in episodes of the TV series The Love Boat (1982 and 1984) and Hotel (1984 and 1987). She also appeared alongside Angela Lansbury in the TV series Murder, She Wrote, guest-starring in three episodes broadcast in 1985, 1990, and 1991. The 1991 episode, titled "Thursday's Child", was her final television role. Miles acted just once more, appearing alongside James Belushi in the film Separate Lives (1995), before retiring from the industry.