The vitamin folate has been largely responsible for a fundamental shift in our perception of the role of vitamins in maintaining health. Ten years ago, two independent clinical trials showed that supplementing a woman’s diet with folic acid before and during early pregnancy reduced the prevalence of neural tube defects (NTDs) by more than 70%. A remarkable aspect was that folic acid supplementation was not correcting a clinical deficiency in most of these women. It was later shown that the risk of having an NTD-affected birth was negatively associated with maternal red cell folate status, and the level of risk varied throughout the normal range, suggesting an interaction of genetic factors with folate nutritional status. It now appears that an insufficient folate status might contribute to risk of developing a variety of medical conditions throughout an individual’s lifetime, from certain congenital malformations and poor pregnancy outcomes to cardiovascular disease, some malignancies, and neurological dysfunction of the elderly. Thus, an alternative view of folate nutrition has emerged. This view goes beyond the idea of a dietary requirement to prevent signs and symptoms of clinical deficiency towards one of achieving an optimal status to reduce risk of certain chronic diseases, and includes the concept that an individual’s genetic make-up may substantially affect the vitamin status that they can achieve without supplements or fortification.