Carbohydrate and fatty acids are major energetic substrates, although amino acid oxidation also permits ATP synthesis. Among several major metabolic differences between lipids and carbohydrate (activation, transport, effect of insulin, etc.), two are of particular importance when considering energy metabolism of critically ill patients: the yield of ATP synthesis and the response to uncoupling. (I) Oxidative phosphorylation yield is higher when NADH is the electron donor (three coupling sites: complex 1, 3 and 4) as compared to FADH2 (two coupling sites: complex 3 and 4). Since the ratio NADH/FADH2 is higher for glycolysis as compared to beta-oxidation, the stoichiometry of ATP synthesis to oxygen consumption is also higher. Lipid oxidation provides more ATP than carbohydrate, but it requires more oxygen per mole of ATP synthesized. (II) The ratio of NADH oxidation versus FADH, oxidation depends on the proton motive force, and lowering proton motive force by uncoupling favours FADH2 oxidation, i.e. lipids versus carbohydrate. In conclusion, lipid oxidation provides a high rate of ATP synthesis even during a mild uncoupling state, but at a high rate of oxygen consumption. If oxygen availability is limited, the major metabolic adaptation to increase the efficiency is represented by a switch from lipid oxidation to glucose oxidation.