In end-stage renal disease (ESRD) both an inappropriately high sympathetic drive and the activation of tissue-based renin-angiotensin systems lead to a complex pattern of comorbidity appearing early on in renal disease. In this context, uremic cardiomyopathy, diabetes, and renal failure display an intimate interaction that critically defines the prognosis in dialysis patients. Importantly, patients with moderate to severe loss of renal function not only carry a high burden of traditional cardiovascular risk factors, but also are exposed to uremia-specific risk factors that in concert induce an excessively increased cardiovascular mortality. Although cardiovascular guidelines may not simply be applicable to ESRD patients —these have invariably been excluded from larger cardiovascular trials—an early cardiological workup appears rational as the prevailing mode of death is characterized by sudden cardiac death and heart failure. This short review will therefore go beyond coronary heart disease, focus on the specific cardiac pathology in renal failure, and summarize the contemporary therapeutic strategies in ESRD.