As the central organ of stress and adaptation to stressors, the brain plays a pivotal role in behavioral and physiological responses that may lead to successful adaptation or to pathophysiology and mental and physical disease. In this context, resilience can be defined as “achieving a positive outcome in the face of adversity”. Underlying this deceptively simple statement are several questions; first, to what extent is this ability limited to those environments that have shaped the individual or can it be more flexible; second, when in the life course does the brain develop capacity for flexibility for adapting positively to new challenges; and third, can such flexibility be instated in individuals where early life experiences have limited that capacity? Brain architecture continues to show plasticity throughout adult life and studies of gene expression and epigenetic regulation reveal a dynamic and ever-changing brain. The goal is to recognize those biological changes that underlie flexible adaptability, and to recognize gene pathways, epigenetic factors and structural changes that indicate lack of resilience leading to negative outcomes, particularly when the individual is challenged by new circumstances. Early life experiences determine individual differences in such capabilities via epigenetic pathways and laying down of brain architecture that determine the later capacity for flexible adaptation or the lack thereof. Reactivation of such plasticity in individuals lacking such resilience is a new challenge for research and practical application. Finally, sex differences in the plasticity of the brain are often overlooked and must be more fully investigated.