Many coenzymes are vitamins that are assimilated in mammals into their active form from precursors obtained from the diet. They are often both rare and reactive rendering the likelihood low that the cell uses a collision-based strategy for their delivery to dependent enzymes. In humans, there are only two known B12 or cobalamin-dependent enzymes: methionine synthase and methylmalonyl-CoA mutase. However, the pathway for intracellular assimilation and utilization of this cofactor is complex as revealed by careful clinical analyses of fibroblasts from patients with disorders of cobalamin metabolism. In the recent past, six of the eight human genes involved in the B12 pathway have been identified and these have yielded important insights into their roles. The recent literature on the encoded proteins is reviewed, and a model for intracellular B12 trafficking is proposed in which B12 is escorted to its target proteins in the cytoplasmic and mitochondrial compartments in complex with chaperones, thereby averting problems of dilution and adventitious side reactions.