The global obesity epidemic is driving metabolic (insulin-resistance) syndrome–related health problems, including an approximately 3- to 4-fold increased coronary heart disease risk. Autonomic dysfunction, ie, increased sympathetic drive and reduced vagal tone, may participate in the pathogenesis and complications of the metabolic syndrome—comprising higher blood pressure (BP), more active renin-angiotensin system, insulin resistance, faster heart rates, excess cardiovascular disease, including sudden death—and possibly aggravate the tendency to weight gain and obesity. Components of the metabolic syndrome that may enhance sympathetic drive include alterations of insulin, leptin, nonesterified fatty acids (NEFAs), cytokines, triiodothyronine, eicosanoids, sleep apnea, nitric oxide, endorphins, and neuropeptide Y (NPY). Of note, high plasma fatty acids are an independent risk factor for hypertension and sudden death. In short-term human studies, fatty acids can raise BP, heart rate, and 1-adrenoceptor vasoreactivity, while reducing baroreflex sensitivity, endothelium-dependent vasodilatation, and vascular compliance. Efforts to further identify the mechanisms and consequences of sympathetic dysfunction in the metabolic syndrome may provide insights for therapeutic advances to ameliorate the excess cardiovascular risk and adverse outcomes...