The peroxisome proliferator-activated receptor gamma (PPARgamma) plays a key role in the regulation of lipid and glucose metabolism. Human genetic evidence supporting this view comes from the study of both common (e.g. the Pro12Ala polymorphism) and rare (loss-of-function mutations) variants in the gene encoding PPARgamma. Indeed, patients harbouring mutant PPARgamma exhibit familial partial lipodystrophy type 3 and an extreme monogenic form of the metabolic syndrome. The recent elucidation of the crystal structure of the full-length PPARgamma-RXRalpha heterodimer bound to DNA has shed new light on the functional consequences of these genetic PPARgamma alterations and provides novel insights as to why different perturbations of receptor function unite in a common pathway of metabolic dysfunction.