In skeletal muscle, in which the metabolic rate can be altered rapidly, a flexible system for fatty acid (FA) utilization is highly desirable. However, for many years it had been thought that blood borne delivery of FA and their rapid diffusion through the plasma membrane provided sufficient FA to meet increased oxidative demands. Our work has shown that FA uptake into muscle occurs via a protein-mediated mechanism involving FA transporters, among which FA translocase (FAT/CD36) is one of the most important (for review see (1)). FAT/CD36 protein expression scales with the oxidative capacity of muscle and with the rate of FA oxidation among metabolically heterogeneous muscles. FAT/CD36 is present at the plasma membrane and in an intracellular depot. During exercise, FAT/CD36 is translocated from this intracellular depot to the plasma membrane, thereby increasing the rate of fatty acid transport into muscle (2). FAT/CD36 is also induced to translocate by AICAR (3), insulin (4) and leptin. Ablation of FAT/CD36 markedly impairs AICAR- and insulin-stimulated fatty acid oxidation and esterification (5), and exercise capacity (-50%). We (7) have also shown that that FAT/CD36 is involved with regulating CPT1- mediated fatty acid uptake by mitochondria, in rodent (6) and human muscle (7) at rest and during exercise. References 1. Bonen, A., et al (2007) Physiology 22, 15, 2007; 2. Bonen, A., et al. J. Biol. Chem. 275, 14501, 2000; 3. Luiken, JJFP, et al. Diabetes 52, 1627, 2003; 4. Luiken, JJFP et al., Am. J. Physiol. 282, E491, 2002; 5. Bonen, A., et al. Am J Physiol in press, 2007; 6. Campbell, SE et al., J. Biol. Chem 279, 36325, 2004; 7. Holloway, GP. et al. J Physiol 571, 201, 2006.