..........Clearly, insulin resistance is not simply a problem of deficient glucose uptake in response to insulin, but a multifaceted syndrome that increases significantly the risk for cardiovascular disease. The links between insulin resistance and the associated dyslipidemia, hypertension, hypercoagulability, and atherosclerosis are numerous and complex. This complexity derives both from the almost certain multiple causes of the insulin resistance syndrome and from the interaction of genes predisposing to insulin resistance with other genes that have their own, independent impact on lipid metabolism, blood pressure regulation, coagulation, and artery wall biology. Nonetheless, I suggest that dysregulation of fatty acid metabolism plays a central role in the development of this phenotype. Thus, the association between insulin resistance and dyslipidemia is clearly initiated by increased FFA release from, or defective uptake of FFAs into, adipocytes. Recent studies linking fatty acids to endothelial dysfunction, together with the clear role of VLDL in the stimulation of PAI-1, further support the view that dysregulation of fatty acid metabolism sits close to the center of the pathophysiology of the insulin resistance syndrome, at least as it relates to risk for cardiovascular disease.