Peroxisome proliferator-activated receptor-gamma (PPARgamma), a fatty acid receptor, has received particular attention as the molecular target of insulin-sensitizing drugs, and as a regulator of lipid accumulation by the coronary artery macrophages known as foam cells. Controversial results have been reported regarding the consequences of PPARgamma activation in the inflammatory response, the progression or improvement of the atherosclerotic lesion, and the identity of target tissues (muscle or fat) for PPARgamma-specific antidiabetic drugs. A clear understanding of how PPARgamma functions in each of these processes is therefore necessary to advance its utility as a therapeutic target. Receptor-dependent and -independent actions of PPARgamma agonists have been carefully examined with a combination of Pparg-knockout mice, PPARgamma-null embryonic stem cells, PPARgamma-specific drugs, and mouse models of atherosclerosis. Through those combined studies, a physiological and therapeutic role for PPARgamma in lipid management by the macrophage has emerged.