The following review indicates that the impact of cobalamin on neurologic disease extends far beyond the traditional myelopathy of classical pernicious anemia. The delineation of a broad spectrum of inherited disorders of cobalamin processing has served to illustrate and precisely define each step in the normal absorption, transport and intracellular metabolism of this essential vitamin. Recent clinical work has extended the boundaries of acquired cobalamin deficiency to encompass a variety of neuropsychiatric disturbances without identifiable concomitant hematologic derangements and emphasized the utility and sensitivity of new laboratory tests. These findings will demand increased vigilance from clinicians so that atypical and subtle cobalamin deficiency states will be readily diagnosed. The wide range of neurologic dysfunction observed in both inherited and acquired disorders of cobalamin metabolism challenges basic scientists to delineate cobalamin’s presumed important role in the normal development and homeostasis of the nervous system.