During the prolonged phase of critical illness, the ongoing hypermetabolic response leads to loss of lean tissue mass. Although the cachexia of prolonged illness is usually associated with low concentrations of anabolic hormones, most endocrine interventions attempting to correct the hormone balance have shown to be ineffective and their indiscriminate use is even harmful. Thus, a detailed understanding of the neuroendocrinology of the stress response is warranted, especially as the acute and chronic phases show remarkable differences. In the acute stress response, low circulating peripheral anabolic hormone levels, despite an actively secreting pituitary, are indicative of peripheral resistance to the anterior pituitary hormones. By contrast, the pulsatile secretion of anterior pituitary hormones is uniformly decreased in the prolonged phase of the disease, leading to proportionally reduced concentrations of peripheral anabolic hormones. As hypothalamic secretagogues can restore the pulsatile secretion of the anterior pituitary and increase peripheral target hormones, tissues are at least partially sensitive to the anterior pituitary hormones in this phase of illness. Therefore, a combination of hypothalamic secretagogues that reactivates the anterior pituitary to a greater extent could be a more physiological and effective strategy to induce anabolism in patients with prolonged critical illness.