Excessive accumulation of fatty acids (FA) or their products, both in the circulation and the tissues, has been implicated in the pathogenesis of several key manifestations of insulin resistance syndrome, including the atherogenic lipoprotein profile, insulin resistance, disturbances in insulin secretion, as well as accelerated apoptosis in pancreatic b-cells and cardiac tissue. In the context of cardiovascular disease and conditions of insulin resistance, these associations provide a reasonable basis for development of strategies, including pharmacological approaches, which correct dysregulation of free fatty acid (FFA) metabolism. Via agonist activation, nuclear receptors (peroxisome proliferator activated receptors [PPARs]) mediate important control over the transcription of many genes involved in FA metabolism. However, there are hardly any detailed in vivo investigations of the effects of PPAR agonists on FFA fluxes and metabolic fate. Here, we summarize our own studies of the effects of PPARg agonists in the obese Zucker rat, a model of insulin resistance and dyslipidaemia. These studies show that PPARg agonists correct many aspects of dysfunctional FA metabolism in obese Zucker rats. Future clinical studies are required to establish the translation of these beneficial effects in experimental animals to patients with insulin resistance, including type 2 diabetes.