Donor red cells are destroyed following transfusion if the patient has or develops clinically significant antibodies. However, some patients, especially those with sickle cell disease can experience life-threatening transfusion reactions despite lack of clinically relevant antibodies. Besides Fc receptors, other immunoreceptors on macrophages such as SIRP-alpha receptor have the potential to mediate red cell clearance. A hyper-activated immune state as a result of the underlying disease may also contribute to increased red cell destruction. In this session, the speakers will review some of the possible mechanisms of red cell clearance following transfusion, describe the role of various macrophage molecules in red cell destruction and highlight use of mouse models of hemolytic transfusion reactions to dissect the mechanisms of red cell clearance in order to develop strategies to stop the destruction.