In an era marked by the increasing prevalence of obesity, diabetes, and cardiovascular disease, the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) has emerged as a transcriptional regulator of metabolism whose activity can be modulated by direct binding of small molecules. As the master regulator of fat-cell formation, PPARgamma is required for the accumulation of adipose tissue and hence contributes to obesity. Yet PPARgamma ligands are clinically effective antidiabetic drugs, although side effects limit their utility. Can PPARgamma be targeted with greater benefit and with less risk to patients? The answer depends upon the basic biology of PPARgamma, and the possibility of selectively modulating the activity of this nuclear receptor in a tissue- and target-gene-specific manner.