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We used a cross-sectional twin design to investigate the genetic and environmental influences on the use of alcohol, tobacco, marijuana, and other drugs and to examine whether the effects of genetic and environmental influences on adolescent drug use are mediated by school-based programs. The Social Developmental Sequence (SDS) model was applied to define theoretically relevant constructs in the use of drugs as well as the influence of school-based programs (SVPs). A total of 1,204 pairs of male-female twins from the Virginia Twin Registry, ages 14-20, completed the questionnaire package that included self-reports of drug use and use of SVPs. Genetic and environmental influences on the use of drugs and SVPs were estimated for the 4 drugs of concern. Prevalence was high on the use of alcohol (46.2%), tobacco (38.1%), marijuana (38.0%), and other drugs (53.8%). Univariate twin analyses indicated that about half of the variance in substance use is due to genetic factors. Correlations among substance use variables were mostly modest. Analyses also showed that heritable influences were partly mediated by SVPs. The SDS model produced measures that define genetically influenced and modifiable risk factors for adolescent drug use. Heritable risk factors such as SVPs need to be targeted in prevention programs. We support programs that include both school-based and community-based interventions. Opinions of the United