One hundred years ago Thomas Addison (1) recognized as a clinical entity the disease known as pernicious anemia. The anemia is characterized by insidious onset, by the presence of abnormally large red blood cells, a deficiency of gastric secretion, and certain gastrointestinal and neurologic disturbances. The designation, pernicious , which implies a fatal outcome, has become inadequate since the advent of liver therapy. It was in 1926 that Minot and Murphy (2) made the important observation that the feeding of whole liver to patients with pernicious anemia results in a relatively rapid remission of most symptoms, only those due to irreversible pathologic changes occurring before liver therapy being refractory to such treatment. Experimental evidence for the value of liver had been demonstrated the year before by Whipple (3) in dogs with hemorrhagic anemia. Although pernicious anemia had been considered by most clinicians as being due to a toxic or infectious agent, it now appeared that a deficiency of a nutritional factor was the cause of the disease. Subsequent studies by Castle and associates (4) clarified somewhat the rel-ationship of food to pernicious anemia. Castle postulated that certain fods, such as eggs or lean beef, contained an factor which when acted upon by the factor, secreted by the normal stomach, yielded the erythrocyte maturation factor or anti-pernicious anemia factor, which was then stored in * Presented before Joint Session of the Science Teaching Societies, American Association for the Advancement of Science, December 28, 1949, New York City. the liver. The basic defect in a patient with pernicious anemia is an inability to produce intrinsic factor in the stomach. If gastric juice from a normal person (containing intrinsic factor) is incubated with beef muscle or another source of extrinsic factor and then administered to a pernicious anemia patient a satisfactory clinical response is obtained just as when liver itself is given. With the knowledge that liver is effective in the treatment of pernicious anemia, investigators from all over the world set out to isolate and identify the active principle therein. Concentrates were made which reduced considerably the size of the dose needed. Some patients, however, objected to the unpalatability of the concentrates as much as they had to the large amounts of whole liver which had to be taken by mouth. Finally it was posible to prepare highly refined liver extracts which were much less expensive than liver itself and which could be given by injection. A more accurate dose could be given by injection and the response by this route of administration was found to be more rapid than when liver or liver preparations were given orally. Furthermore treatment could be given at intervals of two or more weeks instead of daily. In recent years a crystalline vitamin of the B-complex, called pteroylglutamic or folic acid was isolated and then synthesized. This was found to be effective in the treatment of the anemia of pernicious anemia, sprue and nutritional macrocytic anemia. Used in milligram doses it brought about a rise in the