The adrenal gland plays a pivotal role in the stress response since this response involves the hypothalamic-pituitary-adrenal axis (HPAA) and the sympatho-adrenomedullary system (SAMS) as its two principal components. An important relation between the immune system and the other stress response systems is also centered on the adrenal gland. It is well known that the cortex secretes glucocorticoids while the medulla secretes epinephrine, two of the major effects of the stress response. Some other aspects, however, also deserve special consideration: The paracrine effects of the cortical secretion on the medullary cells through the special irrigation system of the gland and reciprocally the influence of the medulla upon the cortex, either by direct close contact or by local innervation. The influence of vascular events also needs to be considered as well as the existence of some local hormonal axis such as those resulting from the local production of renin or CRH in adrenal cells. Some other cells such as mast cells, macrophages and endothelial cells seem to play a role in the regulation of the adrenal cortex and hence in the tuning of the stress response. Stressors stimulate the release of CRH from the hypothalamic paraventricular nucleus inducing the secretion of ACTH from the pituitary and that of corticosteroids from the adrenal cortex. Through the activation of the sympathetic system the adrenal can be stimulated even before adequate levels of ACTH are reached. In conditions of chronic stress the adrenal cortex undergoes an adaptation that allows the hypersecretion of glucocorticoids to occur even without the increment of ACTH.