Donor red blood cells are destroyed following transfusion if the patient has or develops clinically significant antibodies. However, some patients, especially those with sickle cell disease (SCD) 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 hyperactivated immune state as a result of the underlying disease may also contribute to increased RBC destruction. In this session, we will review some of the possible mechanisms of red blood cells 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 RBC clearance in order to develop strategies to stop the destruction.