Discussed are potential roles for neurocognitive function in models of substance misuse prevention. Regional heterogeneity in the time-course of brain development appears to be one contributor to adolescent substance misuse vulnerability as areas of the brain related to reward, pleasure, novelty seeking, and emotion achieve functional maturity much earlier in development than do frontal-cortical areas of the brain responsible for self-regulation of behavior and higher order cognitive decision-making. We review the literature related to the development of neurocognitive systems known to correlate with substance misuse and suggest roles for neurocognition in models of substance misuse prevention outcomes. Implications and future directions for neurocognitive models of substance misuse prevention are also discussed.