Resistance to insulin-stimulated glucose uptake is associated with several cardiovascular disease risk factors, including hypertension, dyslipidemia, and alterations of the blood clotting cascade that accentuate thrombosis. This constellation of risk factors may be recognized at young ages and is at least in part heritable. Recognition of this syndrome dictates that preventive and therapeutic strategies should address overall cardiovascular disease risk. In patients with hypertension or diabetes, additional clinical trials are required to identify those interventions that will most effectively reduce not only overall risk but also definitive cardiovascular disease endpoints.