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Peroxisome proliferator-activated receptor (PPAR)-alpha is a member of a large nuclear receptor superfamily whose main role is to activate genes involved in fatty acid oxidation in the liver, heart, kidney, and skeletal muscle. While currently used mainly as hypolipidemic agents, the cardiac effects and anti-inflammatory actions of PPAR-alpha agonists in arterial wall cells suggest other potential cardioprotective and antiatherosclerotic effects of these agents. This review summarizes current knowledge regarding the effects of PPAR-alpha agonists on lipid and lipoprotein metabolism, the heart, and the vessel wall and introduces some of the insights gained in these areas from studying PPAR-alpha-deficient mice. The introduction of new and more potent PPAR-alpha agonists will provide important insights into the overall benefits of activating PPAR-alpha clinically for the treatment of dyslipidemia and prevention of vascular disease.