Transfusion of stored blood is regarded as one of the great advances in modern medicine. However, during storage in the blood bank, red blood cells (RBCs) undergo a series of biochemical and biomechanical changes that affect cell morphology and physiology and potentially impair transfusion safety and efficacy. Despite reassuring evidence from clinical trials, it is universally accepted that the storage lesion(s) results in the altered physiology of long-stored RBCs and helps explain the rapid clearance of up to one-fourth of long-stored RBCs from the recipient's bloodstream at 24 hours after administration. These considerations explain the importance of understanding and mitigating the storage lesion. With the emergence of new technologies that have enabled large-scale and in-depth screening of the RBC metabolome and proteome, recent studies have provided novel insights into the molecule-level metabolic changes underpinning the accumulation of storage lesions to RBCs in the blood bank and alternative storage strategies to mitigate such lesion(s). These approaches borrow from recent insights on the biochemistry of RBC adaptation to high altitude hypoxia. We recently conducted investigations in genetically modified mice and revealed novel insights into the role of adenosine signalling in response to hypoxia as a previously unrecognised cascade regulating RBC glucose metabolism and increasing O2 release, while decreasing inflammation and tissue injuries in animal models. Here, we will discuss the molecular mechanisms underlying the role of purinergic molecules, including adenosine and adenosine triphosphate in manipulating RBCs and blood vessels in response to hypoxia. We will also speculate about new therapeutic possibilities to improve the quality of stored RBCs and the prognosis after transfusion.