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Adolescent drug use is a serious and persistent public health problem that has been largely impervious to massive efforts to bring it under control. Although recent years have seen a slight drop in rates of adolescent drug use, the percentage of young Americans reporting drug use prior to reaching adulthood remains high. Understanding the origins of adolescent drug use, therefore, has become a national concern with hundreds of studies examining potential risk factors. Despite this knowledge base growing considerably in the past few decades, important gaps in the literature remain that hinder further development in the field. Recent research, for example, has shown that genetic factors are connected to the risk of substance use, but whether genetic influences differentially explain substance use in males and females has yet to be fully explored. The current study addresses this gap in the literature by analyzing a longitudinal, nationally representative sample of individuals residing in the United States. The analyses reveal interesting results regarding the existence of important quantitative and qualitative sex differences in the etiology of substance use. These findings have important implications for future research.