There is still insufficient knowledge about in vivo glutamine metabolism and the regulation of glutamine homeostasis, particularly during metabolic stress. A shortage of glutamine is associated with a poor outcome, whereas for septic patients in the intensive care unit an increased availability of glutamine can prevent mortality and morbidity. Cellular defense mechanisms depend on normal glutamine availability to respond adequately to challenges presented. In clinical practice, treatment of plasma glutamine depletion improves outcome for the critically ill patient. An increased metabolic need for glutamine must be met with an increased consumption of glutamine. Ordinary food is not a sufficient supply of glutamine for the patient with multiple organ failure in the intensive care unit, but that is also true for several other nutrients. It is, therefore, debatable whether an exogenous supply of glutamine should be regarded as a pharmacologic treatment or whether this just represents physiology in stressed states. If a glutamine shortage requires substitution, supplementation to the normal concentration is compensation of a shortage, and the effect is physiological.