This article reviews psychodynamic theoretical claims linking childhood losses to depression later in life and explores contemporary empirical studies that are congruent with those claims. Biologically mediated responses to grief, empirically supported pathways that link loss to depression, and factors that distinguish normal from pathological grief are identified. Trajectories that may lead to the development of psychotic-like, instead of neurotic-like, symptoms of depression are also explored, and empirically supported internal and external vulnerability factors that may lead to depression are reported. Several clinical vignettes are included to exemplify theoretical claims. Implications for assessment and treatment are discussed in light of these findings.