Male and female rodents respond differently to acute stress. We tested our hypothesis that this sex difference is based on differences in stress sensitivity of forebrain areas, by determining possible effects of a single acute psychogenic stressor (1-hr restraint stress) on neuronal gene expression (c-Fos and FosB immunoreactivities), storage of corticotropin-releasing factor (CRF) immunoreactivity, and CRF production (CRF mRNA in situ hybridization) as well as the expression of genes associated with epigenetic processes (quantitative RT-PCR) in the rat paraventricular nucleus (PVN), the oval and fusiform subdivisions of the bed nucleus of the stria terminalis (BSTov and BSTfu, respectively), and the central amygdala (CeA), in both males and females. Compared with females, male rats responded to the stressor with a stronger rise in corticosterone titer and a stronger increase in neuronal contents of c-Fos, CRF mRNA, and CREB-binding protein mRNA in the PVN. In the BSTov, females but not males showed an increase in c-Fos, whereas the CRF mRNA content was increased in males only. In the BSTfu, males and females showed similar stress-induced increases in c-Fos and FosB, whereas in the CeA, both sexes revealed similar increases in c-Fos and in CRF mRNA. We conclude that male and female rats differ in their reactivity to acute stress with respect to possibly epigenetically mediated (particularly in the PVN) neuronal gene expression and neuropeptide dynamics (PVN and BSTov) and that this difference may contribute to the sex dependence of the animal's physiological and behavioral responses to an acute stressor. © 2011 Wiley Periodicals, Inc.