Ghrelin is classically known as a central appetite-stimulating hormone, but has recently been recognized to have a significant role in peripheral tissue energy metabolism. Skeletal muscle is a major site for glucose and lipid disposal. However, the direct effects of ghrelin on this tissue remain understudied. We found that the two major ghrelin isoforms, acylated and unacylated ghrelin, were able to significantly increase skeletal muscle fatty acid oxidation while incorporation of fatty acids into major lipid pools remained unchanged. The increase in fatty acid oxidation was not accompanied by increases in AMP-activated protein kinase or acetyl-CoA carboxylase phosphorylation. Ghrelin isoforms significantly blunted epinephrine-stimulated lipolysis, but had no effect on lipolysis alone. This blunting effect did not appear to be due to decreased HSL phosphorylation. Taken together, these findings suggest that ghrelin isoforms have a direct, acute effect on fatty acid oxidation and lipolysis.