Transcobalamin II is a plasma protein that binds vitamin B12 (cobalamin) as it is absorbed in the terminal ileum and distributes it to tissues. The circulating transcobalamin II-cobalamin complex binds to receptors on the plasma membrane of tissue cells and is then internalized by receptor-mediated endocytosis. A number of genetic abnormalities are characterized either by a failure to express transcobalamin II or by synthesis of an abnormal protein. These disorders result in cellular cobalamin deficiency and megaloblastic anaemia. In this chapter we review the structural and functional properties of transcobalamin II, the receptor for the transcobalamin-cobalamin complex and the clinical disorders that are associated with perturbation of circulating transcobalamin II. In addition, we provide emerging data about the molecular genetics of transcobalamin II which has emanated from our own and other laboratories.