The hypothalamic-pituitary-adrenocortical (HPA) axis is crucial for stress adaptation, regulating the secretion of glucocorticoids to redirect energy resources. The HPA stress response is primarily driven by neural mechanisms, involving the release of corticotropin-releasing hormone (CRH) from hypothalamic paraventricular nucleus (PVN) neurons. Stressor-dependent pathways activate CRH release, with reactive responses involving direct noradrenergic or peptidergic drive and anticipatory responses using oligosynaptic pathways from upstream limbic structures. Anticipatory responses are mediated by disinhibition, where trans-synaptic silencing of tonic PVN inhibition by GABAergic neurons in the amygdala enhances CRH neuronal activity. Glucocorticoids inhibit stress responses through negative feedback mechanisms, acting to diminish drive and promote trans-synaptic inhibition by limbic structures. Chronic stress can lead to various forms of HPA axis activation, including chronic basal hypersecretion, sensitized stress responses, and adrenal exhaustion, depending on factors such as stressor chronicity, intensity, frequency, and modality. Individual responses to acute or chronic stress are influenced by genetics, early life experience, environmental conditions, sex, and age. The context in which stressors occur determines whether responses are adaptive or maladaptive. The review focuses on the regulation of acute and chronic HPA axis responses, highlighting the role of different neural and hormonal mechanisms, and the impact of various factors on stress responses.The hypothalamic-pituitary-adrenocortical (HPA) axis is crucial for stress adaptation, regulating the secretion of glucocorticoids to redirect energy resources. The HPA stress response is primarily driven by neural mechanisms, involving the release of corticotropin-releasing hormone (CRH) from hypothalamic paraventricular nucleus (PVN) neurons. Stressor-dependent pathways activate CRH release, with reactive responses involving direct noradrenergic or peptidergic drive and anticipatory responses using oligosynaptic pathways from upstream limbic structures. Anticipatory responses are mediated by disinhibition, where trans-synaptic silencing of tonic PVN inhibition by GABAergic neurons in the amygdala enhances CRH neuronal activity. Glucocorticoids inhibit stress responses through negative feedback mechanisms, acting to diminish drive and promote trans-synaptic inhibition by limbic structures. Chronic stress can lead to various forms of HPA axis activation, including chronic basal hypersecretion, sensitized stress responses, and adrenal exhaustion, depending on factors such as stressor chronicity, intensity, frequency, and modality. Individual responses to acute or chronic stress are influenced by genetics, early life experience, environmental conditions, sex, and age. The context in which stressors occur determines whether responses are adaptive or maladaptive. The review focuses on the regulation of acute and chronic HPA axis responses, highlighting the role of different neural and hormonal mechanisms, and the impact of various factors on stress responses.