The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor that controls the expression of specific target genes involved in adipogenesis, inflammatory responses, and lipid metabolism. Atherosclerotic plaque progression is influenced by intraplaque inflammation and extracellular matrix deposition. Anti-inflammatory, anti-proliferative and anti-protease activity of PPARgamma may modulate the atherosclerotic process. PPARgamma is expressed in atherosclerotic lesions of human coronary arteries and has direct anti-inflammatory effects in the vascular wall. Thiazolidinediones (TZD) are ligands for PPARgamma used therapeutically to enhance insulin-mediated glucose uptake in persons with type 2 diabetes. These agents may also exert anti-atherogenic effects on cells of the vessel wall including macrophages, vascular endothelium and vascular smooth muscle. This review discusses the impact of PPARgamma and its activators in the numerous processes involved in the formation of atherosclerotic lesions. We provide an overview of in vitro and in vivo data in cell lines, animal models, and humans demonstrating the ways in which PPARgamma activation alters the biology of the arterial wall.