From a transactional developmental perspective, the authors review findings from studies ofanimals and humans regarding a proposed relation between stress system abnormalities and majordepression. The stress system has evolved to promote successful adaptation across the life span,but disruptions in its functioning may increase the risk of pathological outcomes. Emphasis isplaced on the role of prenatal and early postnatal experience in contributing to individualdifferences in postnatal stress reactivity, which may interact with cognitive and psychosocialvulnerabilities to increase susceptibility to later onset of depression. Findings regarding cognitive,psychosocial, and medical sequelae of depression are also reviewed, with a focus on the possiblemediating role of the stress system. The authors highlight the importance of multidisciplinary,longitudinal studies in attempting to gain a deeper understanding of the complex developmentalprocesses involved in the onset and course of depression.