The use of two or more substances in combination, simultaneous polydrug use (SPU), is a particularly dangerous form of drug use that appears to be established by late adolescence. The authors examined the prevalence of SPU in a diverse sample of 12th graders, and identified risk and protective factors for SPU that are present at 10th grade. The authors also tested for differences in SPU across race and gender, and explored the basis for observed differences. The study goals were to determine the extent of SPU problems in different groups and how to address these problems. Twenty-nine percent of participants had engaged in SPU in the past year. The best predictors of alcohol/marijuana SPU were a pro-drug environment, pro-drug beliefs, social deviance, and family disruption; only a pro-drug environment was predictive of hard drug SPU. Women were far less likely to combine marijuana and alcohol than were men. Asian Americans were less likely to combine alcohol and marijuana than were other racial groups, apparenty due to their advantaged standing on all predictors of this behavior. African Americans were less likely to use hard drugs in combination than were other groups. Overall, polydrug use is a substantial problem for older teens. Broader drug-use prevention programs may be sufficient to address SPU involving gateway drugs, but reducing drug availability appears central to addressing hard drug SPU.