Anemia and bleeding are major sources of morbidity and mortality for a broad range of patients, and transfusion is the mainstay of treatment for the consequences of bleeding. The current literature raises, however, many questions about the independent association of poor outcome with transfusion of blood and blood products. In addition, as the availability of safe donors decreases, the costs of processing blood have escalated, mainly in response to increased demands for blood safety. New models for assessing the true costs of transfusion are discussed that allow incorporation and weighing of factors more often obscured in conventional discussions of the cost-effectiveness of transfusion.