Acute stress is known to evoke a discrete pattern of c-fos expression in the brain. The work reported here shows that this pattern is modified in regionally specific ways following repeated stress, and that this can be correlated with changes in telemetered heart rate, core temperature and corticosterone output that occur during adaptation. Intact male rats were restrained for 60 min daily for one or 10 days. Stress-induced tachycardia was maximal 10 min following the onset of restraint, and decreased thereafter. The peak value was not altered by repeated restraint, but levels fell towards baseline values more rapidly with increasing bouts of stress. Core temperature showed marked reduction during the first 10 min of the initial stress, followed by a minor (and not very consistent) overshoot during the remainder of the stress period. In contrast to heart rate, stress-induced hypothermia did not alter during repeated restraint. Corticosterone was raised dramatically immediately following the first 60-min session of restraint, and this was attenuated by repeated stress. Sixty minutes after the end of the first stress session, there was pronounced c-fos expression in the lateral septum, lateral preoptic area, lateral hypothalamic area, all divisions of the hypothalamic paraventricular nucleus, the medial (but not central) amygdala, the locus ceruleus and a brainstem structure (thought to be Barrington's nucleus), compared to rats transferred to the testing room but not restrained. Sixty minutes after the 10th stress session, c-fos expression was markedly decreased in some of these areas compared with the pattern observed after the first stress, especially in the paraventricular nucleus (dorsal and medial parvicellular regions) and in medial amygdala. However, all other areas measured demonstrated a sustained response even after repeated stress. There were no significant differences in c-fos expression in rats repeatedly transferred to the testing room (but not stressed) compared to singly transferred counterparts. These results show that both neuronal and physiological responses adapt to a repeated stress, but that in both cases this has highly specific components. It seems likely that adaptive changes in c-fos expression are associated with those in some features of autonomic and endocrine reactions. It is noteworthy that there is evidence that the lateral septum, in which c-fos expression did not diminish after repeated stress, may be involved in temperature control, whereas the paraventricular nucleus, in which c-fos did alter, has been linked with both cardiac and corticoid regulation.