Cardiovascular disease is the major killer in ESRD. Cardiovascular death risk is at least an order of magnitude higher in ESRD patients, even after adjusting for age and diabetic status. Cardiac failure is a rapidly lethal condition in ESRD patients which appears to mediate much of the adverse prognostic impact of ischemic heart disease. Left ventricular abnormalities are present at initiation of dialysis in about 80% of dialysis patients. These are very highly predictive of future ischemic heart disease, cardiac failure, and death after 2 years on dialysis therapy. Regression of these abnormalities improves prognosis. The associations between many classical risk factors like hyperlipidemia, smoking and hypertension and cardiac outcomes in ESRD are inconsistent. Many factors unique to ESRD and its therapy may be important. In our prospective 10 year study of 433 patients starting dialysis, the following were major risk factors for cardiac disease: hypertension (concentric LVH, LV dilatation, de novo ischemic heart disease, de novo cardiac failure, inverse relationship with mortality); anemia (LV dilatation, de novo cardiac failure and death); hypoalbuminemia (de novo ischemic heart disease, de novo cardiac failure and death). LV abnormalities tended to worsen on dialysis and improve after transplantation suggesting that a uremic environment is cardiotoxic. Many risk factors act in concert to produce cardiovascular disease in ESRD. Many can be treated, suggesting that the huge burden of disease can be reduced considerably.