The measurement of red blood cell survival in the circulation has progressed from the original differential agglutination technique of Ashby to current isotopic and flow cytometric methods. While occasionally useful in the clinic, these methods find widespread use in a number of important research areas, including the evaluation of new red cell storage media in transfusion medicine and studies of the pathophysiology of sickle cell disease and diabetes. In this review, measurement techniques are placed in historical perspective and examined for relative merits and suitable application.