The transfusion of red blood cells (RBCs), although necessary for treatment of anemia and blood loss, has also been linked to increased morbidity and mortality. RBCs stored for longer durations and transfused in larger volumes are often cited as contributory to adverse outcomes. The potential mechanisms underlying deleterious effects of RBC transfusion are just beginning to be elucidated. In this narrative review, we explore the hypothesis that prolonged RBC storage results in elaboration of substances which may function as danger associated molecular pattern molecules that activate the innate immune system with consequences unfavorable to healthy homeostasis. The nature of these chemical mediators and the biological responses to them offers insight into the mechanisms of these pathological responses. Three major areas of activation of the innate immune apparatus by stored RBCs have been tentatively identified: RBC hemolysis, recipient neutrophil priming, and reactive oxygen species production. The possible mechanisms by which each might perturb the innate immune response are reviewed in a search for potential novel pathways through which transfusion can lead to an altered inflammatory response.