We have reviewed the literature on the effect of vitamin B(12) (cobalamin) on development and birth defects. In rodents, administration of antibodies to cubilin, a component of the intestinal receptor responsible for cobalamin absorption, results in a variety of defects including neural tube defects. There is no direct evidence that this is mediated through a direct effect on cobalamin metabolism. Homozygosity for inactive versions of the genes for CUBN coding for cubilin, AMN, coding for amnionless, the MTR gene coding for methionine synthase, or MTRR coding for methionine synthase reductase, is embryonic lethal in mice. Homozygosity for a hypomorphic form of the MTRR gene is associated with increased occurrence of defects. In man, the following have been associated with neural tube defects: decreased maternal serum and amniotic fluid levels of vitamin B(12;) decreased serum levels of cobalamin bound to the serum transport protein transcobalamin; increased levels of homocysteine and methylmalonic acid; and the G allele in mothers and embryos at the 66A>G polymorphism in the MTRR gene. A prospective study to determine whether fortification of food with vitamin B(12) in addition to folic acid might decrease the incidence of birth defects to a greater extent than does fortification with folic acid alone is warranted.