Transfusion of D+ red blood cells (RBCs) into D− recipients, whether through whole blood, RBC, or platelet (PLT) transfusion, can lead to alloimmunization with associated risks of hemolytic reactions from subsequent mismatched transfusion. The incidence of D alloimmunization in various transfused patient populations may be different from that reported in normal subjects or in pregnancy, but prevention of D alloimmunization after mismatched transfusion can be achieved using RhIG. An optimal approach to the use of RhIG, however, has not been identified for the United States. Case histories and studies of volunteers reported over the past 40 years have established that alloimmunization to mismatched RBC transfusion can be successfully prevented with a dose of 20 µg of RhIG per 1 mL of D+ RBCs (per 2 mL of whole blood) when given within a window of opportunity that extends to at least 72 hours. Evidence from prospective studies of RhIG as a therapy for immune thrombocytopenic purpura suggests that such doses can be tolerably given by intravenous injections over short periods, with adverse event rates minimized when pretransfusion medication is given. For mismatched PLT transfusions, the lowest dose of standard preparations of RhIG (e.g., 125 or 300 µg) should be sufficient to prevent alloimmunization given the small D+ RBC volumes involved. This article reviews how our understanding of prevention of alloimmunization in mismatched transfusion has progressed over the years and outlines some practical considerations based on the currently available evidence.