Peroxisome proliferator-activated receptor gamma (PPAR, NR1C3) is a ligand-activated transcription factor belonging to the retinoic acid receptor and thyroid hormone receptor family of nuclear receptors. Classically, these transcription factors regulate expression of target genes by binding to PPAR response elements (PPRE) in the 5 flanking region of target genes as a heterodimer with retinoid X receptors (RXR). PPAR first gained prominence when it was discovered that it was expressed specifically in adipocytes and its expression induced their differentiation. 1 It has now become clear that although expression of PPAR may be the highest in adipose tissue, it is expressed in many, if not all, cell types and tissues. Among the many roles ascribed to PPAR are adipogenesis, insulin action, glucose homeostasis, and lipid metabolism. Other tissue-specific functions for PPAR in liver, muscle, heart, macrophages, bone, and, more recently, the vasculature have been proposed, ascribed mainly from the analysis of cultured cells and a large and rapidly expanding set of tissue-specific PPAR knockouts. The standing of PPAR as a clinically important molecule emerged when it was discovered that PPAR is the molecular target of the thiazolidinediones (TZD) class of antidiabetic agents. 2 Although of understandable interest to diabetes researchers and clinicians, interest among “hypertensionists” increased when it became clear that TZD, in addition to improving glycemic control, tended to lower blood pressure. Many of these studies involved high-risk patients with diabetes or metabolic syndrome and an average decrease of 5 mm Hg systolic blood pressure and 3 mm Hg (diastolic blood pressure [DBP]) was typically reported. According to guidelines from the American Heart Association, 65 million Americans have hypertension and millions of others have prehypertension. Therefore, an analysis of any drug effective at lowering arterial pressure or physiological pathway targeted by that drug involved in regulating arterial pressure deserves serious attention. In this review, I summarize evidence mainly from transgenic and gene-targeted mice suggesting that activation PPAR lowers blood pressure and may do so mechanistically by providing a protective effect on the vasculature. I focus entirely on effects of PPAR in the endothelium and vascular muscle. Such a focus necessitates ignoring, in this forum, substantial literature suggesting that macrophage PPAR plays an important protective role in atherosclerosis and is a potent antiinflammatory. Many other excellent reviews are available on this topic. 3, 4 For full disclosure, although substantial data suggest TZD are cardioprotective, other studies suggest there may be serious adverse effects. 5, 6 The conclusions of these latter studies, however, remain controversial.