Why do some individuals succumb to stress and develop debilitating psychiatric deseases including depression and posttraumatic disorders, whereas others adapt well in the face of adverse events? Resilience is the ability to cope with, learn from, and thrive in the face of adversity. Resilience is built over the life course, beginning early in life, and is based on the remarkable plasticity of the developing and adult brains to a continuously changing environment. Understanding the neural bases of individual and sex differences in responses to stress on brain development and functions is essential to the development of better pharmaceuticals to either promote coping mechanisms (preventive care) or mitigate maladaptive stress responses (curative care). After describing the new view of epigenetics that adds to the old notion that “biology is destiny,” this chapter summarizes some of the underlying mechanisms of stress effects upon the brain and the body and provides a perspective on the emerging contribution of high-throughput technologies and next-generation interventions to develop and enhance resilience