Cardiovascular disease is common and is the major cause of mortality and morbidity in end stage renal disease (ESRD). This article explores some of the many factors responsible for the high prevalence and mortality of cardiac disease in patients with ESRD. The mechanisms for cardiotoxicity in ESRD are multiple and include coronary artery disease, cardiomyopathy, microvascular disease, arrhythmia, valvular disease, cardiac calcification, pericarditis, aortic stiffness, malnutrition, inflammation, abnormal myocardial metabolism. Identifying high-risk patients remains a challenge as many traditional risk factors and screening tools are less predictive of cardiac disease in ESRD. At present, the treatment of high-risk patients is largely based on data from the general population and observational studies of patients with ESRD.