Despite considerable progress during recent years our understanding of how lipid oxidation (LOx) is controlled during exercise remains incomplete. This review focuses on the role of mitochondria and energy state in the control of LOx. LOx increases in parallel with increased energy demand up to an exercise intensity of about 50-60% of VO(2max) after which the contribution of lipid decreases. The switch from lipid to carbohydrate (CHO) is of energetic advantage due to the increased ATP/O(2) yield. In the low-intensity domain (<50%VO(2max)) a moderate reduction in energy state will stimulate both LOx and CHO oxidation and relative fuel utilization is mainly controlled by substrate availability and the capacity of the metabolic pathways. In the high-intensity domain (>60%VO(2max)) there is a pronounced decrease in energy state, which will stimulate glycolysis in excess of the substrate requirements of the oxidative processes. This will lead to acidosis, reduced levels of free Coenzyme A (CoASH) and reduced levels of free carnitine. Acidosis and reduced carnitine may limit the carnitine-mediated transfer of long-chain fatty acids (LCFA) into mitochondria and may thus explain the observed reduction in LOx during high-intensity exercise. Another potential mechanism, suggested in this review, is that Acyl-CoA synthetase (ACS), an initial step in LCFA catabolism, functions as a regulator of LOx. ACS activity is suggested to be under control of CoASH and energy state. Furthermore, evidence exists that additional control points exist beyond mitochondrial FA influx. The nature and site of this control remain to be investigated.