Transfusion of the injured patient with packed red blood cells (PRBCs) is a dynamic process requiring vigilance during the acute resuscitative and recovery phases postinjury. Although adverse events have been reported in 2% to 10% of injured patients, the advent of new detection techniques for viral pathogens has markedly decreased the risk of infectious transmission. However, transfusions are strongly associated with immunosuppression in the host, which may occur days after the initial injury and may lead to bacterial infections. Conversely, early transfusion of stored PRBCs, > 6 units in the first 12 h postinjury, contributes to an early state of hyperinflammation that is a strong, independent predictor of multiple organ failure (MOF) in those patients with intermediate injury severity scores. The roles of prestorage leukoreduction are also reviewed with respect to the promotion of both immunosuppression and hyperinflammation. We further summarize studies with hemoglobin substitutes, whose use may obviate many of the untoward events of transfusion and promise to lead to better outcomes for injured patients.