For many years, the traditional treatment for hospitalized patients in the United States who have developed anemia, whether associated with medical illness, surgical procedures or trauma, has been red blood cell transfusion, despite the absence of supporting data in many patient populations. Emerging evidence suggests that transfusions may, in fact, be associated with risk beyond commonly held concerns of microbial transmission and acute antigen-antibody reactions. The following overview represents a biological paradigm for understanding the relationship between medical illness, surgical procedures, inflammatory states, anemia, red blood cell transfusion and immunothrombotic phenomena among hospitalized patients.