Child abuse is associated with markedly elevated rates of major depression (MDD) in child, adolescent, and adult cohorts. This article reviews preclinical (e.g., animal) studies of the effects of early stress and studies of the neurobiological correlates of MDD in adults and children, and it highlights differences in the neurobiological correlates of MDD and stress at various developmental stages. The preclinical studies demonstrate that stress early in life can alter the development multiple neurotransmitter systems and promote structural and functional alterations in brain regions similar to those seen in adults with depression. Preclinical and clinical studies suggest, however, that long-term neurobiological changes associated with early stress can be modified by familial/genetic factors, the quality of the subsequent caregiving environment, and pharmacological interventions. Little is known about how developmental factors interact with experiences of early stress and these other modifying factors. Moreover, in cases of child maltreatment, the effects of early abuse are often exacerbated by failures in the child protection system and repeat out-of-home placements. Given the number of factors that impact on the long-term outcome of maltreated children, multidisciplinary research efforts are recommended to address this problem—with foci that span from neurobiology to social policy.