Under normal circumstances there is a reciprocal relation between the availability of free fatty acids (FFAs) and glucose in plasma. In the fasted state, FFAs predominate in both availability and the relative contribution to energy production, whereas the same is true for glucose in the fed state. The extent of glucose oxidation is directly determined by its availability, whereas FFAs are normally available well in excess of their rate of oxidation. The rate of FFA oxidation is determined by the rate of transfer into the mitochondria via the carnitine palmitoyltransferase (CPT) enzyme system, which in turn is regulated by the metabolism of glucose. With critical illness the stress response involves mobilization of both plasma glucose and FFAs simultaneously in both the fed and fasted states. In the situation of excess availability of substrates, the metabolism of glucose limits the oxidation of FFAs, thereby channeling those fatty acids into triglyceride (TG) stores in the muscle and the liver. The high FFA concentrations and increased tissue TG stores can limit glucose clearance from the blood, thereby contributing to the development of hyperglycemia. Also, the excessive metabolism of glucose can result in lacticacidemia and can contribute to the depletion of muscle glutamine. The nutritional treatment of such patients must account for these underlying metabolic responses to avoid amplifying potentially detrimental responses to the excess availability of substrates already present in the fasting state.