Liability to persistent health conditions, such as presyndromal psychopathology, chronic biomedical disease, and developmental disorders, is not evenly distributed within groups of children. Rather, a small segment of the childhood population bears a disproportionate burden of the overall risk for mental and physical morbidities. A growing body of work suggests that this excessive risk for disorder is co-determined by: a) compromised early environments, such as those found in impoverished families and communities, b) experiences of subordination and social marginality, and c) a neurobiological sensitivity to social context operating at the levels of behavior, neural circuitry and gene expression. Taken together, these interactive risk factors delineate a biology of misfortune that places some children on developmental trajectories toward lifelong patterns of ill health and unrealized potential.