Peroxisome proliferator–activated receptors (PPARs) play key roles in the regulation of energy homeostasis and inflammation, and agonists of PPARα and -γ are currently used therapeutically. Fibrates, first used in the 1970s for their lipid-modifying properties, were later shown to activate PPARα. These agents lower plasma triglycerides and VLDL particles and increase HDL cholesterol, effects that are associated with cardiovascular benefit. Thiazolidinediones, acting via PPARγ, influence free fatty acid flux and thus reduce insulin resistance and blood glucose levels. PPARγ agonists are therefore used to treat type 2 diabetes. PPARα and -γ agonists also affect inflammation, vascular function, and vascular remodeling. As knowledge of the pleiotropic effects of these agents advances, further potential indications are being revealed, including roles in the management of cardiovascular disease (CVD) and the metabolic syndrome. Dual PPARα/γ agonists (currently in development) look set to combine the properties of thiazolidinediones and fibrates, and they hold considerable promise for improving the management of type 2 diabetes and providing an effective therapeutic option for treating the multifactorial components of CVD and the metabolic syndrome. The functions of a third PPAR isoform, PPARδ, and its potential as a therapeutic target are currently under investigation.