Peroxisome proliferator-activated receptor-γ (PPARγ), 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 PPARγ activation in the inflammatory response, the progression or improvement of the atherosclerotic lesion, and the identity of target tissues (muscle or fat) for PPARγ-specific antidiabetic drugs. A clear understanding of how PPARγ functions in each of these processes is therefore necessary to advance its utility as a therapeutic target. Receptor-dependent and -independent actions of PPARγ agonists have been carefully examined with a combination of Pparg-knockout mice, PPARγ-null embryonic stem cells, PPARγ-specific drugs, and mouse models of atherosclerosis. Through those combined studies, a physiological and therapeutic role for PPARγ in lipid management by the macrophage has emerged.