Blood centers are in the unique position to evaluate large numbers of blood donations for antigen-negative blood types. The limitations with the use of hemagglutination, however, can be circumvented with red cell genotyping. The reagents used for genotyping are synthesized and can be designed for any of the known blood group antigen single nucleotide polymorphisms that are associated with blood group antigen expression. There is interest in the application of mass-scale red cell genotyping of blood donors to find rare phenotypes and rare combinations of antigens. When performed on donors who are predicted to donate again after testing, integrating the genotype information with existing donor data and demographics provides the blood center with real-time information to identify the common clinically relevant blood group antigens demanded by hospital transfusion services. This review outlines a red cell genotype methodology using TaqMan chemistry and existing algorithms and data handling to gain the full value of mass-scale red cell genotyping of blood donors.