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The peroxisome proliferator activated receptor gamma (PPARgamma) is a member in the nuclear receptor superfamily which mediates part of the regulatory effects of dietary fatty acids on gene expression. As PPARgamma also coordinates adipocyte differentiation, it is an important component in storing the excess nutritional energy as fat. Our genes have evolved into maximizing energy storage, and PPARgamma has a central role in the mismatch between our genes and our affluent western society which results in a broad range of metabolic disturbances, collectively known as the metabolic syndrome. A flurry of human and mouse studies has shed new light on the mechanisms how the commonly used insulin sensitizer drugs and PPARgamma activators, thiazolidinediones, act, and which of their physiological effects are dependent of PPARgamma. It is now evident that the full activation of PPARgamma is less advantageous than targeted modulation of its activity. Furthermore, new roles for PPARgamma signaling have been discovered in inflammation, bone morphogenesis, endothelial function, cancer, longevity, and atherosclerosis, to mention a few. Here we draw together and discuss these recent advances in the research into PPARgamma biology.