The hypothalamo-pituitary-adrenocortical (HPA) axis is essential for stress adaptation, regulating glucocorticoid secretion to redirect energy resources. Stress responses are primarily driven by corticotropin-releasing hormone (CRH) from hypothalamic paraventricular nucleus (PVN) neurons, with pathways varying between reactive and anticipatory responses. Anticipatory responses involve disinhibition via GABAergic neurons in the amygdala, while reactive responses are directly driven by sensory inputs. Glucocorticoids inhibit CRH neurons via membrane receptors and provide feedback to limit prolonged activation. Chronic stress can lead to various forms of HPA axis activation, including basal hypersecretion, sensitized responses, and adrenal exhaustion, with outcomes depending on stressor characteristics. Neural mechanisms for chronic stress may differ from acute responses, involving novel limbic and brainstem circuits. Individual responses to stress are influenced by genetics, early life experience, environment, sex, and age. The context of stressors determines whether responses are adaptive or maladaptive. The HPA axis is regulated by multiple systems, including the autonomic nervous system, which activates sympathoadrenomedullary pathways. Glucocorticoids, acting through mineralocorticoid (MR) and glucocorticoid (GR) receptors, regulate energy mobilization, inflammation, and neural function. GR is primarily responsible for feedback regulation, while MR is involved in circadian rhythms. Chronic stress can alter HPA axis function, with effects on adrenal size, sensitivity, and immune organ involution. Stressor specificity determines HPA axis responses, with homeostatic and psychological stressors activating different pathways. Sex differences in HPA axis activity are significant, with estradiol enhancing responses and testosterone inhibiting them. Developmental and aging processes also influence HPA axis function, with early life experiences and maternal care affecting stress reactivity. Corticosteroid binding globulin (CBG) modulates glucocorticoid availability, influencing HPA axis responses. Chronic stress leads to long-term changes in HPA axis function, including increased baseline glucocorticoid release and altered feedback mechanisms. Understanding these dynamics is crucial for managing stress-related disorders.The hypothalamo-pituitary-adrenocortical (HPA) axis is essential for stress adaptation, regulating glucocorticoid secretion to redirect energy resources. Stress responses are primarily driven by corticotropin-releasing hormone (CRH) from hypothalamic paraventricular nucleus (PVN) neurons, with pathways varying between reactive and anticipatory responses. Anticipatory responses involve disinhibition via GABAergic neurons in the amygdala, while reactive responses are directly driven by sensory inputs. Glucocorticoids inhibit CRH neurons via membrane receptors and provide feedback to limit prolonged activation. Chronic stress can lead to various forms of HPA axis activation, including basal hypersecretion, sensitized responses, and adrenal exhaustion, with outcomes depending on stressor characteristics. Neural mechanisms for chronic stress may differ from acute responses, involving novel limbic and brainstem circuits. Individual responses to stress are influenced by genetics, early life experience, environment, sex, and age. The context of stressors determines whether responses are adaptive or maladaptive. The HPA axis is regulated by multiple systems, including the autonomic nervous system, which activates sympathoadrenomedullary pathways. Glucocorticoids, acting through mineralocorticoid (MR) and glucocorticoid (GR) receptors, regulate energy mobilization, inflammation, and neural function. GR is primarily responsible for feedback regulation, while MR is involved in circadian rhythms. Chronic stress can alter HPA axis function, with effects on adrenal size, sensitivity, and immune organ involution. Stressor specificity determines HPA axis responses, with homeostatic and psychological stressors activating different pathways. Sex differences in HPA axis activity are significant, with estradiol enhancing responses and testosterone inhibiting them. Developmental and aging processes also influence HPA axis function, with early life experiences and maternal care affecting stress reactivity. Corticosteroid binding globulin (CBG) modulates glucocorticoid availability, influencing HPA axis responses. Chronic stress leads to long-term changes in HPA axis function, including increased baseline glucocorticoid release and altered feedback mechanisms. Understanding these dynamics is crucial for managing stress-related disorders.