Nearly 15 million units of packed red blood cells and whole blood are transfused annually in the United States alone. Until recently, the major risks from blood transfusion were thought to be transmission of viral infections, and overall, blood transfusion was believed by most providers to be safe. A safe hemoglobin threshold above which red cell transfusion is clearly unnecessary has not been established. This article addresses the numerous problems that surround the use and consequences of blood transfusion, such as hemoglobin and hematocrit levels, oxygenation, storage time, immunomodulation, infection, and anemia. The relevant literature is comprehensively reviewed.