A body of convincing evidence demonstrates that periconceptional folic acid supplements are associated with a reduction in the risk for first occurrences of neural tube defect and for recurrence of neural tube defects among women with a previously affected pregnancy. The mechanism(s) of this protective effect are unknown, and although the effect can be seen with folate doses between 0.4 and 4 mg, the optimal dose remains unknown. The optimal method of ensuring that all women of child-bearing age receive this dose of folate remains in question; supplementation offers the advantage of targeting only the population at risk, whereas food fortification offers the advantage of ensuring compliance in virtually all of the population at risk. The use of periconceptional folic acid can be expected to reduce, but not abolish, the incidence of neural tube defects. Research into the mechanism(s) of the protective effects of folic acid and the underlying biology of neural tube defects is required to address the problem of how to develop therapeutic strategies to further reduce the impact of neural tube defects.