The hypothalamo-pituitary-adrenocortical (HPA) axis is responsible for initiation of glucocorticoid stress responses in all vertebrate animals. Activation of the axis is regulated by diverse afferent input to the hypothalamic paraventricular nucleus (PVN). This review discusses brain mechanisms subserving generation and inhibition of stress responses focusing on the contribution of the limbic system and highlighting recent conceptual advances regarding organization of stress response pathways in the brain. First, control of HPA axis responses to psychogenic stimuli is exerted by a complex neurocircuitry that involves oligosynaptic networks between limbic forebrain structures and the PVN. Second, individual stress-modulatory structures can have a heterogeneous impact on HPA axis responses, based on anatomical micro-organization and/or stimulus properties. Finally, HPA axis hyperactivity pursuant to chronic stress involves a substantial functional and perhaps anatomical reorganization of central stress-integrative circuits. Overall, the data suggest that individual brain regions do not merely function as monolithic activators or inhibitors of the HPA axis and that network approaches need be taken to fully understand the nature of the neuroendocrine stress response.