The nuclear receptor PPARgamma is a central regulator of adipose tissue development and an important modulator of gene expression in a number of specialized cell types including adipocytes, epithelial cells, and macrophages. PPARgamma signaling pathways impact both cellular and systemic lipid metabolism and have links to obesity, diabetes, and cardiovascular disease. The ability to activate this receptor with small molecule ligands has made PPARgamma an attractive target for intervention in human metabolic disease. As our understanding of PPARgamma biology has expanded, so has the therapeutic potential of PPARgamma ligands. Recent studies have provided insight into the paradoxical relationship between PPARgamma and metabolic disease and established new paradigms for the control of lipid metabolism. This review focuses on recent advances in PPARgamma biology in the areas of adipocyte differentiation, insulin resistance, and atherosclerosis.