The severity of striking alterations in the hypothalamic-anterior pituitary-peripheral hormone axes, which are the hallmark of severity of critical illness, is associated with a high risk for morbidity and mortality. Most attempts to correct the hormone balance are ineffective or harmful because of lack of pathophysiologic understanding. Extensive research has provided more insight in the biphasic neuroendocrine response to critical illness: the acute phase is characterized by an actively secreting pituitary but low peripheral effector hormone levels. In contrast, in prolonged critical illness, uniform suppression of the neuroendocrine axes, predominantly of hypothalamic origin, contributes to low serum levels of the respective target-organ hormones.