Glucose-6-phosphate dehydrogenase deficiency serves as a prototype of the many human enzyme deficiencies that are now known. Since its discovery more than 50 years ago, the high prevalence of the defect and the easy accessibility of the cells that manifest it have made it a favorite tool of biochemists, epidemiologists, geneticists, and molecular biologists as well as clinicians. In this brief historical review, we trace the discovery of this defect, its clinical manifestations, detection, population genetics, and molecular biology.