The present study utilizes longitudinal data from a high-risk community sample to examine the unique effects of genetic risk, parental knowledge about the daily activities of adolescents, and peer substance use on emerging adult substance use disorders (SUDs). These effects are examined over and above a polygenic risk score. In addition, this polygenic risk score is used to examine gene-environment correlation and interaction. The results show that during older adolescence, higher adolescent genetic risk for SUDs predicts less parental knowledge, but this relation is nonsignificant in younger adolescence. Parental knowledge (using mother report) mediates the effects of parental alcohol use disorder (AUD) and adolescent genetic risk on risk for SUD, and peer substance use mediates the effect of parent AUD on offspring SUD. Finally, there are significant gene-environment interactions such that, for those at the highest levels of genetic risk, less parental knowledge and more peer substance use confers greater risk for SUDs. However, for those at medium and low genetic risk, these effects are attenuated. These findings suggest that the evocative effects of adolescent genetic risk on parenting increase with age across adolescence. They also suggest that some of the most important environmental risk factors for SUDs exert effects that vary across level of genetic propensity.