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Older studies of humans seem to suggest a correlation between free fatty acid (FFA) turnover and oxidation on the one hand and plasma FFA concentration on the other hand during submaximal exercise. However, recent studies, in which higher concentrations of plasma FFA have been reached during prolonged submaximal exercise, have revealed a levelling off in net uptake in spite of increasing plasma FFA concentrations. Furthermore, this relationship between FFA concentration and FFA uptake and oxidation is altered by endurance training. These recent findings in humans support the notion from other cell types that transmembrane fatty acid transport is not only by simple diffusion, but predominantly carrier-mediated. During prolonged submaximal knee-extension exercise it has been demonstrated that the total oxidation of fatty acids was approximately 60% higher in trained subjects than in nontrained subjects. The training-induced adaptations responsible for this increased utilization of plasma fatty acids by the muscle could be located at several steps from the mobilization of fatty acids to skeletal muscle metabolism in the mitochondria. In this paper regulation at the transport steps and also at various metabolic steps is discussed.