Vitamin B12 is sequestered, tailored, and delivered via an elaborate trafficking pathway from its point of entry into the cell to the two known enzymes that utilize it as a cofactor: cytoplasmic methionine synthase (MS), and mitochondrial methymalonyl-CoA mutase. Clinical genetics studies on patients with inborn errors of cobalamin (Cbl) metabolism led to the identification of at least nine genes and provided early insights into the B12 trafficking pathway. Mutations in the cytoplasmic methylcobalamin (MeCbl) branch lead to homocystinuria, while mutations in the mitochondrial 5′-deoxyadenosylcobalamin (AdoCbl) branch lead to isolated methylmalonic aciduria. Studies on the mitochondrial chaperones have provided detailed mechanistic and structural understanding into the AdoCbl branch of the trafficking pathway. In contrast, little was known about the MeCbl branch, how vitamin B12 is delivered to methionine synthase and the roles of two chaperone proteins–CblC and CblD–in this process.The function of the CblD chaperone was unknown, and it was previously reported to be incapable of binding B12. However, we recently discovered that CblD binds B12 and does so via an unusual cobalt-sulfur bond, which is rare in Nature. The existence of this rare coordination chemistry was confirmed by X-ray crystal structures of the CblD-B12 complex, and the CblC-B12-CblD complex which provides structural insights into how B12 might be transferred from these chaperones to methionine synthase.