Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the superfamily of nuclear receptors. It binds and is activated by natural polyunsaturated fatty acids, eicosanoids, synthetic thiazolidinediones and related analogues. Biological effects exerted by PPARgamma ligands are mostly concerned with differentiation processes, sensitization to insulin and atherogenesis, and are paradigmatically ascribed to PPARgamma transactivation of PPARgamma-responsive genes. The PPARgamma paradigm and its consequences in humans are analyzed here in terms of the tissue specificity of PPARgamma, loss and gain of function mutants of PPARgamma, PPARgamma-responsive genes and clinical effects of PPARgamma ligands. Differentiation, as well as some of the atherogenic effects induced by PPARgamma ligands, does conform to the PPARgamma paradigm. However, sensitization to insulin as well as some of the antiatherogenic effects of PPARgamma ligands is not accounted for by PPARgamma activation, thus calling for an alternative target for insulin sensitizers.