Management of the conventional cardiovascular risk factors is insufficient to prevent the dramatic increase in atherosclerotic cardiovascular morbidity and mortality in patients with renal failure. Folate recently received attention as a potential alternative treatment option to decrease the excess cardiovascular risk in the uremic population. Folate administration is the principal treatment modality for hyperhomocysteinemia. Hyperhomocysteinemia is prevalent in more than 85% of patients with end-stage renal disease (ESRD) and is independently associated with increased odds for atherosclerotic cardiovascular disease. Several attempts have been made to normalize homocysteine levels in uremic patients with folate-based vitamin regimens. Although supraphysiologic doses of folic acid afford greater reductions in homocysteine levels than standard doses, the response to treatment is generally only partial and the large majority of ESRD patients have residual hyperhomocysteinemia. Several defects in folate metabolism have been described in uremia, which may explain the relative folate resistance in patients with renal failure, but their clinical relevance remains uncertain. It appears unlikely that the hyperhomocysteinemia in ESRD can be cured solely with folic acid supplements, since folate does not affect the prolonged plasma elimination of homocysteine, which is the primary defect in homocysteine metabolism in uremia. Folate restores endothelial dysfunction, associated with hyperlipidemia, diabetes and hyperhomocysteinemia. The beneficial effect appears to be independent of its homocysteine-lowering capacity and is possibly related to an improved bioavailability of nitric oxide. However, folate has failed to improve endothelial dysfunction in uremic patients. In the ESRD population, multiple metabolic and hemodynamic abnormalities adversely affect endothelial function. In addition, irreversible structural vascular disease already may be present. Folate should, therefore, probably be an integral part of an "endothelial protective regimen," consisting of lipid-lowering agents, antihypertensives and antioxidant vitamins and started very early in patients with renal failure. Before large-scale folate administration can be recommended, effects on hard endpoints of cardiovascular disease need to be demonstrated in randomized trials. Such trials are currently underway in patients with normal renal function at high risk for cardiovascular disease, and one trial has recently been initiated in stable renal transplant recipients.