Abstract: Metabolism cycles daily between the fed and fasted states. The pathways of energy production are reversible and distinct. In the anabolic (fed) state, the liver stores glucose as glycogen, and fatty acid/triglyceride synthesis is active. In the catabolic (fasted) state, the liver becomes a glucose producer, lipogenesis is slowed, and fatty acid oxidation/ketogenesis is activated. The rate‐limiting step for the latter is vested in the carnitine/carnitine palmitoyltransferase (CPT) system, and the off/on regulator of this is malonyl CoA. The AMP‐induced protein kinase primarily determines the concentration of malonyl CoA. Four other systems have significant influence: two on fatty acid oxidation and two on lipogenesis. Peroxisome proliferator‐activated receptor γ‐1α, a master regulator of metabolism, induces hepatic gluconeogenesis and fatty acid oxidation in the catabolic phase. Deficiency of stearoyl CoA desaturase, although having no role in gluconeogenesis, powerfully induces fatty acid oxidation and weight loss despite increased food intake in rodents. Major stimulators of lipogenesis are carbohydrate‐responsive element binding protein and the Insig system. The malonyl CoA‐regulated CPT system has been firmly established in humans. The other systems have not yet been confirmed in humans, but likely are active there as well. Activation of fatty acid oxidation has considerable clinical promise for the treatment of obesity, type 2 diabetes, steatohepatitis, and lipotoxic damage to the heart.