In recent years the concept has been explored that the pathologies of depression and schizophrenia originate during intrauterine life. Several animal models have been developed to investigate the etiopathogenesis of both depression and schizophrenia. However, most of these models have focussed only on single aspects of the corresponding pathology, whereas integrated models using a ‘neural systems’ approach are missing. Over recent last years, our laboratory has developed two novel animal models related to depression and schizophrenia based on such a neural systems approach, using prenatal stress (PS) and prenatal low-dose X-irradiation (PLDI) as damaging agents. This paper provides a comprehensive overview on the cellular and molecular mechanisms mediating the damaging influence of PS and PLDI on the developing brain, and discuss these novel animal models in the context of the relevant literature. Both models provide rationales for future prophylactic interventions in perinatal and adult life, developed on the basis of a better understanding of the underlying mechanisms.