Peroxisome proliferator-activated receptors (PPAR) belong to the nuclear receptor superfamily of ligand-activated transcription factors. PPAR-alpha, first of its three subtypes (alpha, beta, gamma) has traditionally been considered an important regulator of lipid metabolism while its role in the regulation of insulin sensitivity has not been recognized until recently. Here we summarize the experimental and clinical studies focusing on the role of PPAR- alpha in the regulation of insulin sensitivity. In most of the experimental studies the activation of PPAR-alpha in rodents leads to improvement of insulin sensitivity by multiple mechanisms including improvement of insulin signaling due to a decrease of ectopic lipids in non-adipose tissues and decrease of circulating fatty acids and triglycerides. In contrast, the effect of PPAR-alpha agonist in humans is much less pronounced probably due to a lower expression of PPAR-alpha relative to rodents and possibly other mechanisms. Further clinical studies using more potent PPAR-alpha agonists on a larger population need to be performed to evaluate the possible role of PPAR- alpha in the regulation of insulin sensitivity in humans.