Fifty years ago, William B. Castle described the properties of intrinsic factor. By so doing, he advanced the first acceptable theory of the pathogenesis and pathophysiology of pernicious anemia. Enveloping Castle's discovery were prevalent ideas in the medical community of the time, such as the importance of nutritional factors in the pathogenesis of disease, and the intriguing possibility that many disorders could be ameliorated or even cured by administration of a “missing” substance. When viewed in a contemporary perspective, Castle's observations of a half century ago are remarkable examples of ingenuity and single-minded dedication to uncovering the pathogenetic mechanism of a previously fatal disorder.