An alarming high proportion of youth experience at least one kind of stressor in childhood and/or adolescence. Exposure to early life stress is associated with increased risk for psychopathology, accelerated biological aging, and poor physical health; however, it is important to recognize that not all youth who experience such stress go on to develop difficulties. In fact, resilience, or positive adaptation in the face of adversity, is relatively common. Individual differences in vulnerability or resilience to the effects of early stress may be represented in the brain as specific patterns, profiles, or signatures of neural activation, structure, and connectivity (i.e., neurophenotypes). Whereas neurophenotypes of risk that reflect the deleterious effects of early stress on the developing brain are likely to exacerbate negative outcomes in youth, neurophenotypes of resilience may reduce the risk of experiencing these negative outcomes and instead promote positive functioning. In this chapter we describe our perspective concerning the neurobiological mechanisms and moderators of risk and resilience in adolescence following early life stress and integrate our own work into this framework. We present findings suggesting that exposure to stress in childhood and adolescence is associated with functional and structural alterations in neurobiological systems that are important for social-affective processing and for cognitive control. While some of these neurobiological alterations increase risk for psychopathology, they may also help to limit adolescents’ sensitivity to subsequent negative experiences. We also discuss person-centered strategies that we believe can advance our understanding of risk and resilience to early stress in adolescents. Finally, we describe ways in which the field can broaden its focus to include a consideration of other types of environmental factors, such as environmental pollutants, in affecting both risk and resilience to stress-related health difficulties in youth.