Patients with end-stage renal disease (ESRD) are at extreme cardiovascular risk. At least half of all patients starting dialysis therapy have overt cardiovascular disease (CVD). In addition, recent studies suggest annual incidence rates for new-onset cardiac failure, peripheral vascular disease, ischemic heart disease (IHD), and stroke of approximately 7%, 7%, 5%, and 1%, respectively. High-level exposure to traditional risk factors, such as smoking and dyslipidemia, hemodynamic overload factors, such as anemia and hypertension, and a myriad of metabolic factors related to uremia are all likely to play a role. There has been explosive growth in observational studies and a heartening, if less dramatic, increase in risk factor intervention trials, suggesting that risk factor modification can lead to meaningful benefit.