Maternal depression is one of the most common prenatal complications, and prenatal maternal depression predicts many child psychopathologies. Here, we apply the fetal programming hypothesis as an organizational framework to address the possibility that fetal exposure to maternal depressive symptoms during pregnancy affects fetal development of vulnerabilities and risk mechanisms, which enhance risk for subsequent psychopathology. We consider four candidate pathways through which maternal prenatal depression may affect the propensity of offspring to develop later psychopathology across the life span: brain development, physiological stress regulation (hypothalamic–pituitary–adrenocortical axis), negative emotionality, and cognitive (effortful) control. The majority of past research has been correlational, so potential causal conclusions have been limited. We describe an ongoing experimental test of the fetal programming influence of prenatal maternal depressive symptoms using a randomized controlled trial design. In this randomized controlled trial, interpersonal psychotherapy is compared to enhanced usual care among distressed pregnant women to evaluate whether reducing prenatal maternal depressive symptoms has a salutary impact on child ontogenetic vulnerabilities and thereby reduces offspring's risk for emergence of later psychopathology.