As befits a system essential for survival, neuroendocrine regulation of the hypothalamic--pituitary--adrenocortical (HPA) axis is characterized by tight control as well as plasticity. Stimulus-specific afferents code for specific hypothalamic corticotropin (ACTH) secretagogues, which have combinatorial effects on ACTH secretion, resulting in a glucocorticoid response that is tailored to stimulus intensity. Chronic stress-induced stimulation of HPA activity alters ACTH secretagogue expression and hypothalamic afferent activity to maintain adrenocortical responsiveness. Rigorous control of circadian HPA activity optimizes the balance between beneficial and adverse effects of glucocorticoids (largely mediated by glucocorticoid receptors) by minimizing circadian nadir glucocorticoid secretion (an effect mediated by mineralocorticoid receptors). HPA activity also is controlled by other glucocorticoid-regulated factors, such as immune and metabolic status. Dysregulation of these control mechanisms is likely to contribute to a variety of diseases.