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This article addresses the complex relationship between childhood trauma and adolescent substance use. Drawing on evidence from neurodevelopmental, psychological/emotional, behavioral, and social research, we determined that childhood trauma, which includes early life stress, adverse childhood experiences (ACEs), and toxic stress, can upset brain development, emotion regulation, and stress-response systems, thereby creating lasting vulnerabilities. These neurological changes both generate and interact with behavioral traits such as impulsivity, poor coping, and emotional dysregulation, thus increasing the risk of substance use as a dysfunctional coping strategy. Social and environmental factors, such as caregiver substance use, peer influences, and community-level disadvantage, further compound these effects. However, individual traits, including effortful control and supportive relationships can attenuate these risks. Moreover, evidence-based interventions that address integrated, trauma-informed, and developmentally appropriate approaches have demonstrated promise in reducing the risks of adolescent substance use among trauma-exposed youth. The article concludes by calling for more conceptual integration across disciplines, longitudinal studies, and culturally responsive prevention, intervention, and treatment approaches.