The metabolic response to critical illness promotes catabolism, which mobilizes substrates for energy. Initially the hypothalamic-pituitary-adrenal axis is stimulated, but later there appears to be anterior pituitary depression. Despite this, the early increase in plasma cortisol levels is usually maintained by means independent of (falling) corticotropin levels. Some patients, however, develop acute adrenal insufficiency and appear to benefit from replacement exogenous glucocorticoid. However, identifying such patients is often difficult. The replacement of other deficiencies may not be in the patients’ interests. For example, leptin, a stress-related hormone, has multiple effects, some seemingly advantageous and others detrimental in critical illness. Its overall influence and significance remains unclear.The health of gut mucosa and the inflammatory response might be improved or influenced to the (presumed) benefit of the patient by agents such as glutamine, arginine, some eicosanoids, and exogenous nucleic acids. Such “immunonutrition” appears to improve mortality and other measures of outcome in surgical intensive care unit patients and those with sepsis.