Cardiovascular disease is a major cause of morbidity and mortality in chronic renal failure (CRF). The endothelium plays a central role in the control of many aspects of vascular function, and abnormalities may contribute to the generation of atherosclerosis. The endothelium produces a wide range of regulatory molecules which, in health, function in concert to provide a carefully balanced anti-atherogenic environment. Endothelial dysfunction has been repeatedly demonstrated in renal failure, is present in the absence of anatomically obvious disease and appears to be useful in the prediction of morbidity and mortality in other cardiovascular risk groups. One of the most intensively studied and important mediators of endothelial function is nitric oxide (NO), whose production is reduced in CRF. A number of possible mechanisms for reduced NO bioavailability have been investigated including substrate limitation, competitive inhibition of NO synthase by endogenous NO synthase inhibitors known to accumulate in renal failure, and premature quenching of NO by free radicals present in high concentrations in this group. A clearer understanding of the pathogenesis of endothelial dysfunction in CRF has potential clinical implications. It may provide avenues for therapeutic interventions before the onset of clinically obvious cardiovascular disease in this high-risk patient group.