Red blood cells (rbcs) have a definite life-span in circulation, 120 days in humans (and 60 days in rat). This involves the turnover of the equivalent of 2 x 10 (11) rbcs per day in a normal adult. Many time-dependent physical, chemical, as well as biochemical and immunologic changes are associated with in vivo aging of rbcs in circulation. The major difficulty has been to unravel the complex picture and assign the primary signal responsible for the sequestration of the senescent rbc from circulation. Our current hypothesis based on the results of studies from many laboratories including our own is that it involves the progressive desialation of the most abundant sialoglycoprotein on rbc surface, glycophorin A. The complete desialation of glycophorin results in the exposure of multiple galactose-beta (1, 3) N-acetylgalactosamine disaccharide residues on the rbc surface. These sites are recognized by the reticuloendothelial system, and result in the sequestration of those desialated senescent rbcs from circulation. This review summarizes the evidence for and against the immediate acceptance of this hypothesis.