The ability of an organism to respond to stressful stimuli is fundamentally important to that organism’s continuing survival. Recognition of a stressor elicits a range of physiological changes that enable the organism to cope and to facilitate the restoration of homeostasis. Many of these physiological changes are mediated via activation of the hypothalamo–pituitary–adrenocortical (HPA) axis and the consequent secretion of glucocorticoids (GCs) by the adrenal gland. Stimulation of the HPA axis is triggered by neural and humoral mechanisms that converge on the parvocellular neurones in the hypothalamic paraventricular nucleus (PVN) and cause release of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) into the hypothalamo–hypophyseal portal complex for transportation to the anterior pituitary gland. Here, these neurohormones bind to specific CRH and AVP receptors (CRH-R1 and V1b, respectively) on corticotroph cells to induce the release of corticotrophin (adrenocorticotrophic hormone [ACTH]) into the systemic circulation. ACTH acts within the adrenal glands to increase the synthesis and release of GCs, cortisol (in man and other primates) and corticosterone (in rodents). The secretion of these steroid hormones is further regulated by complex negative feedback effects of the GCs themselves on the pituitary gland, hypothalamus and extra-hypothalamic centres in the brain (e.g. hippocampus, brainstem). GCs were originally named on the basis of their influence on metabolic processes, specifically the generation of glucose from protein and lipids. However, GCs also exert a plethora of effects that together serve to maintain homeostasis. GCs thus prepare the organism to respond to stress and also protect the organism from the stress itself, in part by limiting the pathophysiological responses (e.g. inflammation) to the stress that, if left unchecked, may themselves threaten homeostasis.