The way in which experience sculpts developing neural circuitry is one of the most intriguing questions in developmental neurobiology. Evidence has been accumulated that epigenetic factors affect the development of brain and behavior in a much more pronounced way than previously appreciated. However, the cellular mechanisms of such experience-driven developmental changes are far from being understood. The present study provides the first evidence that stress in utero represents an epigenetic factor that can considerably interfere with the development of neuronal morphology in the rodent limbic system. In recent years, the role of psychobiology in understanding abnormal behaviors has become increasingly important. There has been increased awareness that various forms of pathological behaviors in humans might be the outcome of adverse or traumatic experiences, such as stress, occuring early in life. For instance, stress experienced by a mother during pregnancy can act as a predisposing risk factor in the development of schizophrenia, depression, autism and attention-deficit-disorder in the offspring. Similarly, there is considerable evidence indicating that the separation of infant from the mother during the first weeks of their life may lead to behavioral problems at adulthood. Our working hypothesis postulates that exposure to stress during critical developmental periods interferes with the development of neuronal morphology and the establishment and refinement of synaptic circuits. Based on our hypothesis, the aim of this study was to identify the impact of prenatal stress and neonatal handling on the development of neurons and their synaptic networks in the rodent limbic system. The limbic system is a target for hormones involved in stress response and has been implicated in several behavioral and psychiatric disorders that are exacerbated or precipitated by stress exposure. Thus the assessment of the effects of stress on the limbic system may have important implications for the causes and prevention of disorders due to dysfunctional limbic system. This study shows pronounced changes in the morphology of pyramidal and granular neurons in response to prenatal stress. Prenatal stress resulted in significantly lower spine density in the orbitofrontal and anterior cingulate cortices relative to the untreated control animals. In addition, there was a significant reduction in the total dendritic length and arborization in the orbitofrontal and anterior cingulate cortices of males, and the CA3 and CA1 hippocampal areas of both sexes as well as in the basolateral nucleus of males. The present study also provides evidence that the effect of prenatal stress is sexually dimorphic. The neuronal morphology of males and females is altered differentially by prenatal stress. This study further indicated that the neuronal alterations induced by prenatal stress are prevented and/or reversed by neonatal handling. Neonatal handling prevented and/or reversed prenatal stress-induced neuronal alterations in a sex, region and dendrite-specific manner. The present study also demonstrated that the separation of infants from the mothers during the early weeks of their life caused significant alterations in the morphology of pyramidal and granular neurons, which markedly differed between the sexes. Finally, this study revealed that there are considerable sex differences in the neuronal morphology of untreated control animals. The findings of this study provide a neuroanatomical substrate for the behavioral deficits described in prenatally stressed animals. Stress-induced morphological alterations might underlie or contribute to the behavioral impairments caused by stress.