Among adolescents and young adults, the mechanism relating substance use and risky sexual behavior remains ambiguous. Conducting a selective review of related literature, this article examines the association between substance use and sexual risk-taking. In particular, this article explores potential mechanisms through which substance use may impact risky sexual behavior. Given the inconsistency in the literature, important, often omitted factors such as mental health and social networks may play a crucial role in mediating this relationship. The article concludes by discussing the practice and policy implications of these considerations.