Leptin stimulates long chain fatty acid (LCFA) oxidation in skeletal muscle; however, the mechanisms through which this occurs remain unclear. The present study examined whether the fatty acid transporter FAT/CD36 is required for leptin to stimulate LCFA oxidation in skeletal muscle. While palmitate oxidation increased normally in isolated soleii from WT animals when treated with leptin, leptin's ability to stimulate palmitate oxidation was impaired in the FAT/CD36 null soleii. The effects of the AMPK activator, AICAR, on palmitate oxidation in soleii were also FAT/CD36 dependent. The lack of a leptin effect can not be accounted for by altered AMPK or ERK1/2 activation, as leptin-induced AMPK or ERK1/2 activation did not differ between genotypes. Collectively, these data demonstrate that FAT/CD36 is an integral component of the leptin-induced stimulation of fatty acid oxidation, likely via the recruitment of FAT/CD36 to the plasma membrane to facilitate the entry of LCFA into the muscle cell.