Although readily treatable with vitamin B12, pernicious anemia continues to captivate investigative endeavors of those interested in the pathophysiology and pathogenesis of this disorder. Notable advances have been made in understanding properties of intrinsic factor, vitamin B12-binding proteins, structure and de novo synthesis of vitamin B12, mechanism of action of vitamin B12-dependent enzymes in man, and metabolic consequences of reduced activities of these enzymes in pernicious anemia. Similarly, newer morphological observations have given information regarding pathogenesis of some of the cytological abnormalities found in megaloblasts, and recent cytochemical studies have shed light on abnormalities of nuclear and cytoplasmic constituents in vitamin B12-deficient cells. Both cellular and humoral factors may contribute to immune-mediated processes in pernicious anemia, although as yet, it has not been established with certainty that pernicious anemia is an autoimmune disorder. As we look ahead, it will be important to define the process or processes responsible for atrophic gastritis, which is the pathophysiological basis of pernicious anemia. Likewise, advances in biophysics used in the study of cell membranes, cell surface phenomena, and metallic ion transport may find applicability in the study of pernicious anemia and perhaps provide further insights into metabolic abnormalities responsible for the development of megaloblastosis.