Normal rats respond to the stress of intermittent air blasts applied for 3 days by thymus involution, a 3-fold rise in plasma corticosterone, and an increased level of pituitary ACTH. Centrally as well as anteriorly placed lesions of the hypothalamus prevent the stress-induced rise in pituitary ACTH; but in rats bearing anterior lesions, the increase in plasma corticosterone and reduction in thymus weight in response to the airblasts are still fully apparent. Lesions in the lateral septal area or in the anterior cingulate gyrus cause increased adrenal and pituitary weights and a higher water intake in the stressed animals, while preventing or reducing thymus involution and the stress-evoked elevation in plasma corticosterone. The 2 sites of the limbic system exert opposite effects on pituitary ACTH, however, causing abnormally high basal levels in septal-and low levels in cingulate-lesioned rats. The finding that pituitary ACTH-levels, and changes in these levels, need not be correlated with changes in plasma corticosterone and thymus weights suggests that different mechanisms regulate ACTH-synthesis and release. The observations indicate, further, that ACTH-release, in response to a stress, can be unaffected by lesions in the anterior hypothalamus and preoptic area, but may be greatly impaired by destruction of 2 areas in the limbic system, suggesting anatomical connections between the neurons contributing to the latter 2 areas and those postulated to elaborate corti -cotrophin-releasing factors.