Background Adolescence is a critical biological, psychological, and social developmental stage involving heightened risk for substance use and associated adverse consequences. This review, synthesizing emerging findings on this complex topic, is intended to inform research and clinical care focused on adolescents. Methods Literature searches were conducted using PubMed, yielding a cross‐section of observational and interventional studies focused on adolescent substance use. Findings were organized and categorized to cover key areas of epidemiology, neurobiology, prevention, and treatment. Findings Adolescent substance‐related attitudes and use patterns have evolved over time, informed by adult and peer behaviors, public policy, media messaging, substance availability, and other variables. A number of risk and resiliency factors contribute to individual differences in substance use and related consequences. Advances in observational techniques have provided enhanced understanding of adolescent brain development and its implications for substance use. Prevention efforts have yielded mixed results, and while a number of adolescent‐targeted evidence‐based treatments for substance use disorders have been developed, effect sizes are generally modest, indicating the need for further research to enhance prevention and treatment outcomes. Conclusions Substance use in adolescence is heterogeneous, ranging from normative to pathological, and can lead to significant acute and long‐term morbidity and mortality. Understanding risk and resiliency factors, underlying neurobiology, and optimal developmentally sensitive interventions is critical in addressing substance‐associated problems in adolescence.