We outline an epigenetic approach to understanding the relation between simple dispositional characteristics and complex problem behaviors, with a focus on adolescent substance use. Epigenetic theory predicts that effects of temperament are mediated through self-control and risk-taking tendency, isomorphic attributes that are based in temperament but represent developmental elaborations of these characteristics. We describe how the research program has confirmed predictions from epigenetic theory, addressed additional questions embodied in the theory, and clarified the multiple pathways from temperament characteristics to life stress, social relationships, and motives for substance use. In a final section, we discuss implications for the study of problem behavior and psychopathology.