The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the stress response by regulating the release of glucocorticoids from the adrenal cortex. Corticotropin-releasing factor (CRF) initiates a cascade of events that lead to the activation of the HPA axis, which is further modulated by various feedback mechanisms. Glucocorticoid feedback inhibition is crucial in regulating the magnitude and duration of glucocorticoid release. The HPA axis is also regulated by a diverse group of afferent projections from limbic, midbrain, and brain stem nuclei, as well as noradrenergic neurons, sympathetic adrenomedullary circuits, and parasympathetic systems. This review discusses the role of the HPA axis in integrating adaptive responses to stress and identifies key neuronal and endocrine systems that contribute to its regulation and maintenance of homeostasis in the face of aversive stimuli.The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the stress response by regulating the release of glucocorticoids from the adrenal cortex. Corticotropin-releasing factor (CRF) initiates a cascade of events that lead to the activation of the HPA axis, which is further modulated by various feedback mechanisms. Glucocorticoid feedback inhibition is crucial in regulating the magnitude and duration of glucocorticoid release. The HPA axis is also regulated by a diverse group of afferent projections from limbic, midbrain, and brain stem nuclei, as well as noradrenergic neurons, sympathetic adrenomedullary circuits, and parasympathetic systems. This review discusses the role of the HPA axis in integrating adaptive responses to stress and identifies key neuronal and endocrine systems that contribute to its regulation and maintenance of homeostasis in the face of aversive stimuli.