Numerous studies across several population groups have indicated that insulin resistance plays a central role in the development of type 2 diabetes mellitus (T2DM). Moreover, this disorder is also strongly associated with other metabolic syndromes, including hypertension, dyslipidemias and polycystic ovarian syndrome (PCOS). Recent advances have demonstrated that pharmacological agents of the thiazolidinedione class can reverse insulin resistance and profoundly improve many of these associated symptoms. These effects have been documented in a variety of genetic and acquired animal models of insulin resistance, as well as in numerous clinical trials in patients with insulin resistance. These compounds appear to enhance insulin action by modulating the activity of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) gamma. This activation results in changes in the expression of a number of genes that are critically involved in glucose and lipid metabolism, as well as in insulin signal transduction. While precise events that occur downstream from PPAR gamma modulation remain uncertain, new insights are emerging from knockout studies in mice and the identification of genetic variants in humans. These findings indicate that there is still much to learn about the molecular biology and physiology of these interesting receptors, and that research in this area can lead to more effective and safer drugs to treat insulin resistance and associated syndromes.