The hypothalamo-pituitary-adrenocortical (HPA) axis is a primary stress-response system in all vertebrates. The end-products of HPA activation, glucocorticoids, serve the general function of redirecting bodily resources to meet a real or perceived challenge. However, prolonged glucocorticoid secretion has deleterious effects on metabolism, immune function and behaviour, making control of HPA activity a priority for the organism. This control is exerted in large part by limbic structures in the brain. Our studies indicate that the amygdala, hippocampus and prefrontal cortex play major roles in regulating HPA axis to acute stress. The amygdala is primarily stress excitatory, whereas the hippocampus has an inhibitory influence on HPA activity. The role of the prefrontal cortex is considerably more complex; its prelimbic region is primarily stress inhibitory, whereas the infralimbic region may participate in stress activation. All of these regions exert their influence via subcortical relays to hypothalamic paraventricular nucleus (PVN) neurons controlling the HPA response, allowing convergence of information from multiple limbic sources prior to the PVN. In contrast, chronic stress-induced enhancement of HPA axis activation is associated with neuroplastic changes at multiple levels, including limbic forebrain sites, brainstem systems and the PVN proper. It is likely that chronic stress-induced alterations in limbic-PVN circuitry play a major role in stress-related HPA axis abnormalities and are involved in the pathophysiology of numerous stress-related disease states, such as depression and PTSD.