There are notable risks associated with alcohol, cigarette, and marijuana use during adolescence. Yet, there is no single cause for adolescent substance use. The etiology of substance use is known to develop over time, across multiple levels of influence. Informed by developmental perspectives, this review aims to provide an overview of biological (e.g., genetic, neuroimaging), individual (e.g., temperament, behavior problems), and social (e.g., parents, peers) factors that increase risk for and protection against this multifaceted phenomenon. Additionally, emerging areas of research are highlighted, as well as preliminary work examining the etiology of adolescent substance use across multiple levels of influence. Understanding early factors associated with the emergence of adolescent substance use can help inform prevention programming to reduce subsequent cognitive impairments and psychopathology. Adaptive individualized interventions addressing various domains linked to adolescent substance use in real-time are likely to have significant utility given the numerous pathways to adolescent substance use.