In response to stressors, the central nervous system of livestock (and other mammalian species) evokes physiological responses that ultimately result in activation of the hypothalamo-pituitary-adrenocortical (HPA) axis and the sympatho-adrenal axis. The responses of these major systems are presumed to have adaptive and homeostatic value during periods of stress. The major hormone regulating the synthesis and secretion of adrenal glucocorticoids is ACTH. In sheep, cattle, and pigs, both corticotropin-releasing hormone (CRH) and vasopressin (VP) participate in the regulation of secretion of ACTH, and the two peptides seem to interact to enhance that secretion. In cattle and pigs, CRH is the more potent peptide, whereas VP is the more potent in sheep. In addition to its better-known role in regulating pituitary function, CRH also may participate as a neurotransmitter acting centrally to enhance sympathetic activation of the adrenal medulla. Many experimental models of stress have been evaluated that reliably activate the HPA axis and the sympatho-adrenal medullary axis, and some of these model systems also reduce functions of cells of the immune system. Recent data support an important role of stressor-activation of the sympathetics rather than increased glucocorticoids per se in modulating some measures of immune function in response to stress. Thus, current dogma of glucocorticoids as the primary mediator of stressor-associated alteration in immune function of domestic livestock may require reevaluation.