This study sought to expand the modest literature investigating gene x environment interactions in the prediction of substance use. Our sample consisted of 591 male twins from the Minnesota Twin Family Study. Their relative genetic risk was estimated from their parents' substance-related diagnoses and their environmental risk from their affiliations at age 11 with social groups likely to either encourage or discourage substance use. At age 14, the boys' own substance use was assessed. We hypothesized both main effects and an interaction between our genetic- and environmental-risk variables in the prediction of substance use by this young age. We further theorized that the boys' inherited risk might take the form of temperament, specifically externalizing tendencies. Using regression analyses and biometrical modeling, we corroborated earlier research by finding evidence for a significant interactive effect in the etiology of substance use. Our results suggest that low levels of environmental risk may buffer against the potentially unfavorable effects of high familial risk; however, when environmental risk is high, the degree of familial risk is consequential. We were not able to support our second hypothesis; rather, temperament predicted substance use only through shared environmental factors.