Although a reduction in incidence of neural tube defects is unequivocally linked to adequate folate status, evidence is also mounting associating folate with other fetal malformations. The emerging discoveries about single nucleotide polymorphisms have given new insight into folate biochemistry, enabling more precise understanding of how genetic variations influence folate-dependent pathways in embryogenesis. Findings suggest that folate status may be partly under genetic control, and may involve a "cocktail effect" resulting from interactions among genes, nutrients, and enzymes. Despite major laboratory advances, much of the human evidence comes from observational studies, and questions linger that cannot be definitively answered without randomized clinical trials.