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• For human non-RhD RBC alloantigens immunogenicity increases as copy number decreases. • Copy number affects mechanisms of alloimmunization in mouse models. • In humans and mice, very low copy number alloantigens are weakly or nonimmunogenic. • In mice very low copy numbers become tolerogenic, which is untested in humans. • Interpretation of mouse studies must include transgene properties and mouse genetics. RBC alloimmunization remains a significant barrier to ongoing transfusion therapy leading to morbidity, and in extreme cases mortality, due to delayed or insufficient units of compatible RBCs. In addition, the monitoring and characterization of alloantibodies, often with multiple specificities in a single patient, consumes substantial health care resources. Extended phenotypic matching has mitigated, but not eliminated, RBC alloimmunization and is only logistically available for specialized populations. Thus, RBC alloimmunization remains a substantial problem. In recent decades it has become clear that mechanisms of RBC alloimmunization are distinct from other antigens and lack of mechanistic understanding likely contributes to the fact that there are no approved interventions to prevent RBC alloimmunization from transfusion. The combination of human studies and murine modeling have identified several key factors in RBC alloimmunization. In both humans and mice, immunogenicity is a function of alloantigen copy number on RBCs. Murine studies have further shown that copy number not only changes rates of immunization but the mechanisms of antibody formation. This review summarizes the current understanding of quantitative and qualitative effects of alloantigen copy number on RBC alloimmunization. [ABSTRACT FROM AUTHOR]