Substance abuse and dependence are among the nation's leading health issues, leading to more illnesses, disabilities, and deaths than any other modifiable health condition. Substance use among youth is of particular concern, as rates are higher than among any other age group and because early use is associated with a higher risk of later abuse and dependence and a higher incidence of related risk-taking behavior. Thus, a better understanding of the causes of substance use problems is a central issue. The primary goal of this study was to examine genetic and environmental predictors of youth alcohol and drug abuse and dependence. This study expands upon extant research by being the first to utilize a genetic risk score (GRS) approach to examine the joint effect of four dopaminergic genetic polymorphisms on substance abuse and dependence, by incorporating cumulative measures of environmental risk and promotive factors, and by examining gene-environment interactions (GxEs) and gender differences in substance use predictors, thus allowing for a more comprehensive assessment of environmental and genetic influences than has previously been attempted. Analyses were conducted on a national longitudinal sample of 1,396 Caucasian youth who participated in surveys and DNA sampling in the National Longitudinal Study of Adolescent Health, with individuals followed from adolescence (ages 12-18) into early adulthood (ages 24-32). Logistic regression analyses examined main and interactive effects of cumulative environmental risk and promotive factors and genetic risk scores on clinically significant alcohol and drug abuse and dependence in early adulthood. Analyses were conducted separately for males and females to examine gender differences in substance use predictors. Results show that a dopaminergic GRS index significantly predicted the likelihood that female, but not male, youth will meet clinical criteria for substance abuse and dependence, even after accounting for cumulative environmental influences. No evidence of GxE was found. These results provide a better understanding of the etiology of substance abuse and dependence and provide evidence of the utility of GRS methods for studying genetic influences on substance use behaviors.