In 1960 Berson and Yalow published a method for the radioimmunoassay (RIA) of plasma insulin based on the concept that the extent to which unlabeled insulin displaces labeled insulin from anti-insulin antibody is proportional to the concentration of unlabeled insulin. The RIA for insulin has greatly increased knowledge of the physiology of glucose homeostasis and of the diverse causes of diabetes mellitus. Beyond this, the insight on which the RIA—or,more broadly, the competitive protein-binding assay—is based has provided the means to measure nanomolar or picomolar concentrations of a vast array of compounds in plasma and tissues. Directly or indirectly, the RIA has profoundly affected every branch of medicine.This essay reviews the ideas that were current in the medical research community when Berson and Yalow began their work and the observations and reasoning process that led them to their seminal discovery.