Neural tube defects (NTD) are common congenital malformations leading to severe disability or even death. The causes of NTD are multifactorial, including genetic predisposition, nutritional and environmental risk factors, and other maternal conditions. Some countries have introduced mandatory or at least voluntary folic acid fortification as an effective measure to reduce NTD, whereas others support periconceptional supplementation of women of childbearing age. Countries with mandatory fortification achieved a significant increase in folate intake and a significant decline in the prevalence of NTD. This was also true for supplementation trials. However, the magnitude of the decline depends on the initial NTD rate. This review clearly shows that not all cases of NTD can be prevented by increasing the folate intake. Other relevant causes of NTD, which are largely disregarded, have also to be taken into account in research and consultation to reduce the risk and economic burden of NTD.