Hyperhomocysteinemia has been linked to an increased risk for cardiovascular (CV) disease since 1969. Recent epidemiological and cohort observations continue to confirm this relationship, provided the homocysteine concentration is elevated. This elevation in homocysteine concentration and increased CV disease risk are particularly strong in patients with renal disease. Hyperhomocysteinemia is also related to declining status of vitamins B6 and B12, folate, and in some cases riboflavin. This relationship between vitamins and homocysteine concentration has provided the basis for clinical trials targeting CV risk reduction by vitamin supplementation. This review describes the evidence behind vitamin supplementation as it pertains to homocysteine status and make recommendations for vitamin intake management in patients with hyperhomocysteinemia, including those patients with renal disease.