The red blood cells (RBCs) aging process is considered as an issue of special scientific and clinical interest. It represents a total of unidirectional, time-dependent but not-necessarily linear series of molecular events that finally lead to cell clearance1. Under normal circumstances, all human RBCs live approximately 120±4 days in blood circulation, implying the existence of tightly regulated molecular mechanism(s), responsible for the programming of the lifespan and the nonrandom removal of senescent RBCs2,3. Although the RBCs have already been used as a model for aging study1, the molecular participants, as well as the signalling pathways involved, are not yet completely clarified. RBCs storage under blood bank conditions is far from being considered analogous to the physiologic in vivo aging process. The putative implicated in vivo signalling pathways are expected to be more-or-less preserved under in vitro conditions, nevertheless slightly modulated, in response to a totally different environment. A storage period of up to 35–42 days at 4 °C probably is not a “congenial interlude” of the physiological maturity process and definitely does not represent an ignorable time period, compared to the RBCs lifespan. Stored RBCs age without the normal adjacency of other cells or plasma, which continuously provide them with survival factors and signals and, moreover, they are obligated to share their living space with their own and other cells’ wastes. Since no clearance mechanisms seem to function, senescent RBCs are probably sentenced to “survive” for a longer period than they were probably programmed for. Although there is evidence suggesting that storage disturbs the physiological RBC aging process4–7, the mechanistic basis of the aging progress inside the blood unit and the functional reactivity of the modified RBCs in vivo, remain still elusive. Given the fundamental need for safe and efficient transfusions, the clinical impact of stored blood, as a function of the storage parameters, has attracted considerable attention. Clinical trials that focus on the potential adverse clinical consequences of transfusing older storage-age RBCs units vs. younger ones have already been reported8. Apart from the skepticism around their design and execution9, these studies indicate the necessity of thorough examination of the storage effect on packed RBCs, before analyzing their potential impact on the clinical outcome. This review focuses on the current knowledge on aging and death signalling pathways operating in both in vivo systems and stored RBCs and suggests future directions in the preservation science, helpful for addressing what seem to be the current critical questions in transfusion medicine.