Open neural tube defects (NTDs) result from failure of the embryonic process of neural tube closure. This chapter discusses pathophysiology and preventative strategies within each of these recognized subgroups: folate, chromosomal, single gene defects, genetic syndromes, diabetes and obesity, medications and smoking, hyperthermia, amniotic bands, twinning, genes and environment. The greatest success story in NTD prevention is folate supplementation. Through individual supplementation and population-based strategies such as food fortification there has been between a 20% and 70% reduction in NTDs reported across all countries actively supplementing. Diabetes and obesity are potentially modifiable risk factors for NTDs; however, despite general health campaigns regarding the health risks of obesity it remains an ever increasing problem amongst reproductive aged women. Medication and smoking exposures are amenable to prevention with health education advice and further research into safer medication use in pregnancy.