In recent years, red blood cells (RBCs) have finally received well-deserved attention from scientists in the field of transfusion medicine. These biconcave-shaped oxygen-carrying cells were often ignored by cell biologists for being" too simple", due to their lack of intracellular organelles and DNA, and for being relatively unresponsive to their external environment. They were often regarded as an annoying source of contamination from haemoglobin when processing tissues or isolating white blood cells. Special attention was given to studies of RBC response to cold storage and cryopreservation, which gave rise to the widely used, and perhaps obsolete, term of" the RBC storage lesion" 1. It all made sense: prolonged cold storage (6 weeks in the USA) of RBC units does not fully suspend animation, as undesirable metabolic reactions may occur that ultimately compromise cell function and their ability to survive in the bag or later in the patient circulation2. Among the many stress signals associated with the storage lesion, the amount of spontaneous haemolysis and the release of redox active and toxic free haemoglobin have been shown to steadily increase with storage time3, 4. Key preclinical studies using transfusion models in small or large mammals strongly suggested that prolonged RBC storage (42 days in most studies) is associated with increased risk of vasoconstriction mediated by haemoglobin consumption of nitric oxide, oxidative injury, sepsis, and accumulation of non-transferrin bound iron in the circulation4-9. These observations, along with retrospective studies of age of blood transfusions in humans, led to several international randomised clinical trials that evaluated patient outcomes in response to short-term (1-16 days storage) vs longterm (approximately 21-28 days of storage in most studies) RBC storage10-13. The majority of these clinical trials failed to demonstrate any difference in the primary outcomes being evaluated (such as mortality) in relation to storage duration. If RBC ageing in the bag does not fully explain variations in the quality of RBC units or adverse clinical outcomes in transfused patients, what else is out there?