Abstract: Depression is a mental illness closely associated with stress, characterized by high prevalence and disability rates. Many studies have indicated that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is closely related to the pathogenesis of depression. In recent years, researchers have developed various drugs targeting different components of the HPA axis, including glucocorticoid receptor antagonists, corticotropin-releasing hormone receptor 1 antagonists, and FK506-binding protein 51 inhibitors. This review summarizes the research progress on antidepressants that can target the HPA axis, aiming to provide insights and references for further development of antidepressant drugs.