A great part of the population appears to have insufficient folate intake, especially subgroups with higher demand, as determined through more sensitive methods and parameters currently in use. As the role of folate deficiency in congenital defects, e.g. in cardiovascular and neurodegenerative diseases, and in carcinogenesis has become better understood, folate has been recognized as having great potential to prevent these many disorders through folate supplementation or fortification for the general population. Folates are essential cofactors in the transfer and utilization of one-carbon groups in the process of DNA-biosynthesis with implications for genomic repair and stability. Folate acts indirectly to lower homocysteine levels and insures optimal functioning of the methylation cycle. Homocysteine was shown to be an independent risk factor for neurodegenerative and cardiovascular disease, which includes peripheral vascular disease, coronary artery disease, cerebrovascular disease and venous thrombosis. In fact, it was long believed that the beneficial effects of folate on vascular function and disease are related directly to the mechanism of homocysteine-diminution. Recent investigations have, however, demonstrated beneficial effects of folates unrelated to homocysteine-diminution, suggesting independent properties. One such mechanism could be free radical scavenging and antioxidant activity, as it is now recognized that free radicals play an important role in the oxidative stress leading to many diseases. It was found that folic acid and, in particular, its reduced derivates act both directly and indirectly to produce antioxidant effects. Folates interact with the endothelial enzyme NO synthase (eNOS) and, exert effects on the cofactor bioavailability of NO and thus, on peroxynitrite formation. Folate metabolism provides an interesting example of gene-environmental interaction.