During disease states, the endocrine axes exhibit different levels of activity according to the severity of illness. These various alterations have been widely investigated. Indeed, evidence indicates that the anterior pituitary is dysfunctional in these states, especially when multiple organ dysfunction syndrome is present, impacting both adrenal and thyroid glands, but also secretion of estrogen, growth hormone, insulin-like growth factor-1, and prolactin. In a majority of these cases, substitutive treatment is not obviously beneficial, inappropriate secretions being considered as adaptive responses to stressful events. The hypothalamic-pituitaryadrenal axis appears to play the most important role in the regulation of inflammation during septic shock. Many factors modulate this axis. Some are well known. Others, such as vasopressin and apelin, are newly ascribed. Therapeutic issues in critically ill patients still remain controversial and are ardently debated, especially with regard to the needs and practical use of corticosteroids in septic shock. This article focuses on actual knowledge, mechanisms, definitions, and therapeutic recommendations, as well as on areas of uncertainty relative to adrenal gland insufficiency in septic shock.