Cardiac disease is common and is the major killer in end-stage renal disease (ESRD). Cardiac failure is a highly malignant condition in ESRD patients. Cardiac failure mediates most of the adverse prognostic impact of ischemic heart disease. Left ventricular (LV) abnormalities are already present at initiation of dialysis therapy in approximately 80% of patients. These abnormalities (ie, systolic dysfunction in approximately 15%, LV dilatation with preserved systolic function in 30%, concentric LV hypertrophy [LVH] in 40%) independently predict ischemic heart disease and cardiac failure, and are the largest baseline predictor of mortality after 2 years on dialysis therapy. The associations between classical risk factors (eg, hyperlipidemia, smoking, hypertension) and cardiac outcomes in ESRD are inconsistent. "Uremic" risk factors represent a nascent, but potentially important field. In our prospective 10-year study of 433 patients starting renal replacement therapy, we identified the following as major independent risk factors for cardiac disease: (1) hypertension (concentric LVH, LV dilatation, ischemic heart disease, cardiac failure, inverse relationship with mortality); (2) anemia (LV dilatation, cardiac failure, death); and (3) hypoalbuminemia (ischemic heart disease, cardiac failure, death). Transplantation dramatically improved LV abnormalities, suggesting that a uremic environment is cardiotoxic. Multiple risk factors act in concert to produce cardiac disease in ESRD; many of these are avoidable, suggesting that the enormous burden of disease can be reduced considerably.