The specific negative clinical manifestations associated with the transfusion of stored red blood cells (RBCs) and the corresponding mechanisms responsible for such phenomena remain poorly defined. Our recent studies document that leukoreduced older RBC units potentiate transfusion-related toxicity in trauma patients. It is our hypothesis that the transfusion of relatively older blood impedes microvascular perfusion. The central mechanisms proposed to mediate this microcirculatory alteration include: 1) the loss of RBC-dependent control of nitric oxide-mediated homeostasis concerning vasodilation and 2) immune cell and complement activation. In this review, we outline the background for our hypothesis and detail our current investigations toward the understanding of this pathophysiology. © 2011 American Association of Blood Banks.