Transfusion of RBCs is often clinically necessary--and life-saving--for anemic patients. RBCs can be stored for up to 42 days between the time of donation and the time of transfusion. For many years, investigators have studied the biochemical changes that occur in RBCs stored before transfusion (the RBC "storage lesion"). More recently, clinical studies have suggested that RBC units stored for long periods (often described as > 14-21 days) may mediate adverse effects in the recipient, leading to morbidity and mortality. Unfortunately, these effects are difficult to identify and study because there are no agreed-upon mechanisms for these adverse events and few good assays to study them in individual transfusion recipients. We have proposed the hypothesis of insufficient NO bioavailability (INOBA) to explain the adverse events associated with transfusion of older RBC units. INOBA postulates that the combination of impaired NO production and increased NO scavenging by stored RBCs, together with reduced NO synthesis by dysfunctional endothelial cells, collectively reduce NO levels below a critical threshold in vascular beds. In this situation, inappropriate vasoconstriction occurs, leading to reduced blood flow and insufficient O(2) delivery to end organs. If confirmed, the INOBA hypothesis may lead to improved methods for blood storage and collection, as well as new screening and matching tools for blood donors and transfusion recipients.