A protective effect of folate against the development of neural tube defects (NTDs), specifically, anencephaly and spina bifida, is now well recognized, having been established by a chain of clinical research studies over the past half century. This article summarizes the more important of these studies, which have led to the current situation in which all women capable of becoming pregnant are urged to ingest folic acid regularly. The recommended intakes are 4 mg/d for those at high risk (by virtue of a previous NTD pregnancy outcome) and 0.4 mg/d for all others. However, a reduction in NTD births did not follow promulgation of these recommendations, and so folic acid fortification was mandated in the United States and some other countries. Although some controversy remains about the adequacy of fortification levels, the process was followed by significant improvement in folate indexes and a reduction of 25-30% in NTD frequency (about one-half of the proportion of cases assumed to be responsive to folate). The folate-NTD relation represents the only instance in which a congenital malformation can be prevented simply and consistently. Nevertheless, several research gaps remain: identification of the mechanism by which the defect occurs and how folate ameliorates it; characterization of the relative efficacy of food folate, folic acid added to foods, and folic acid by itself; delineation of the dose-response relations of folate and NTD prevention; and more precise quantification of the dose needed to prevent recurrences.