Although adolescents are developmentally distinct from adults, they often receive addiction treatment based on adult models. This is problematic because adolescents face significantly different conditions in addiction treatment, including distinct basic biological and neurodevelopmental stages, unique sociodevelopmental concerns, distinctive addiction trajectories, and, in turn, disparate treatment goals and outcomes. In sum, it can be difficult for even savvy clinicians to know how to approach addiction treatment with this important age group. In an effort to help clinicians and researchers consider substance use via a neurodevelopmental lens, we approached this review with 4 goals: (i) characterize the prevalence, and related health and safety implications of substance use within this age group; (ii) identify the nature of the adolescent brain, including characteristic features of this phase of neurodevelopment relevant to adolescent substance use treatment; (iii) provide an overview of current adolescent addiction interventions and avenues to improve clinical treatment and clinical research efforts for adolescents; and (iv) examine the intersection between the nature of the developing brain and adolescent substance use, and utilize that information to inform alternative routes and directions for substance use treatment in this critical age group. This review concludes by offering a novel neurodevelopmental model and framework to examine substance use interventions, along with a series of recommendations to optimize adolescent substance use treatment and clinical research.