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Glucocorticoids (GCs) are essential for the maintenance of homeostasis and enable the organism to prepare for, respond to and manage stress, either physical or emotional. Cortisol, the principal GC in humans, is synthesized in the adrenal cortex. It is released in the circulation in a pulsatile and circadian pattern. GC secretion is governed by hypothalamus and pituitary. The hypothalamus senses changes in the external and internal environment that may disrupt the homeostatic balance of the organism (i.e. stressors), and responds by releasing corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) from parvocellular neurons projecting from the paraventricular nucleus to the median eminence. These neurohormones are released into the anterior pituitary where they act synergistically via specific receptors (CRH-R1 and V1B receptor, respectively) to trigger the release of the adrenocorticotropic hormone (ACTH) from the corticotrope cells into the systemic circulation. In turn, ACTH exerts its actions on the adrenal cortex via specific receptors, type 2 melanocortin receptors (MC2-R), to initiate the synthesis of cortisol, which is released immediately into the systemic circulation by diffusion. Hypothalamic CRH and AVP, pituitary ACTH and adrenal GCs comprise the hypothalamic-pituitary-adrenal (HPA) axis. In this brief review, the HPA axis and the various factors that regulate its function are described.