Objective: To provide an overview of the genetic epidemiology of substance use and misuse in adolescents. Method: A selective review of genetically informative research strategies, their limitations, and key findings examining issues related to the heritability of substance use and substance use disorders in children and adolescents is presented. Results: Adoption, twin, and extended-family designs have established there is a strong heritable component to liability to nicotine, alcohol, and illicit drug dependence in adults. However, shared environmental influences are relatively stronger in youth samples and at earlier stages of substance involvement (e.g., use). There is considerable overlap in the genetic influences associated with the abuse/dependence across drug classes, and shared genetic influences contribute to the commonly observed associations between substance-use disorders and externalizing and, to a lesser extent, internalizing psychopathology. Rapid technologic advances have made the identification of specific gene variants that influence risks for substance-use disorders feasible, and linkage and association (including genomewide association studies) have identified promising candidate genes implicated in the development of substance-use disorders. Conclusions: Studies using genetically informative research designs, including those that examine aggregate genetic factors and those examining specific gene variants, individually and in interaction with environmental influences, offer promising avenues not only for delineating genetic effects on substance-use disorders but also for understanding the unfolding of risk across development and the interaction between environmental and genetic factors in the etiology of these disorders. (Contains 2 figures.)