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Prior research reveals a host of risk factors related to adolescent illicit substance use. In addition, researchers have explored the intervening mechanisms that may explain these associations, but not all pathways have been sufficiently considered. In this study, we build an argument that sleep duration—and in particular getting less than the recommended amount of sleep—may partially explain the effects of multiple risk factors (i.e., bullying victimization, unstructured socializing, neighborhood disorder, family social control, family conflict) on substance use. Adolescents who experience these risk factors may experience difficulties in achieving adequate amounts of sleep, and this sleep deprivation should in turn be associated with heightened substance use. We test these arguments with data collected from a large sample of Florida middle school and high school students. In considering these issues, this study offers potentially new insights on the predictors of sleep deprivation and the consequences it may have for critical aspects of adolescent development.