Recent scientific and technological advances have brought us closer to being able to apply a true biopsychosocial approach to the study of resilience in humans. Decades of research have identified a range of psychosocial protective factors in the face of stress and trauma. Progress in resilience research is now advancing our understanding of the biology underlying these protective factors at multiple phenotypic levels, including stress response systems, neural circuitry function, and immune responses, in interaction with genetic factors. It is becoming clear that resilience involves active and unique biological processes that buffer the organism against the impact of stress, not simply involve a reversal of pathological mechanisms. Here, we provide an overview of recent progress in the field, highlighting key psychosocial milestones and accompanying biological changes during development, and into adulthood and old age. Continued advances in our understanding of psychological, social, and biological determinants of resilience will contribute to the development of novel interventions and help optimize the type and timing of intervention for those most at risk, resulting in a possible new framework for enhancing resilience across the life span.