Several learning theory based models propose that substance users may have conditioned reactions to stimuli (cues) associated with substance use and that these reactions may increase the probability of relapse. The conditioned withdrawal, conditioned compensatory response, and appetitive motivational models were evaluated in light of empirical evidence from cue reactivity studies with alcoholics, smokers, opiate users, and cocaine users. The nature of the stimuli that elicit reactivity and the nature of the responses elicited are most consistent with an appetitive motivational model and do not appear to support the other two models. A few studies have been conducted or are underway that investigate the use of cue exposure with response prevention as a treatment to decrease cue reactivity. Preliminary work with alcoholics, opiate users and cocaine users is promising but insufficient evidence exists to evaluate this approach. The implications for theory and treatment are discussed.