The rates of onset for several forms of psychopathology peak during adolescence, which coincides with the refinement of brain circuitry attuned to expanding social-contextual interactions, stressors, and settings. While some adolescents experience mental health difficulties, most do not develop significant problems. Conceptual work suggests that brain-based individual differences in adolescents' neurobiological susceptibility to their social contexts play a role in the development of psychopathology and well-being. In this article, I summarize evidence supporting the idea that individual differences in brain structure and function moderate the relation between adolescents' social-contextual experiences and psychopathology. I discuss why this approach is important in developmental research designed to identify adolescents at greatest risk for psychopathology or poised for positive outcomes, as well as those who may benefit most from intervention.