Human leukocyte antigen (HLA) is the major human histocompatibility system and is also known as transplant antigen because it is closely related to organ/tissue transplantation rejection, therefore, the degree of HLA compatibility between donors and recipients is closely related to rejection, transplantation success and long-term graft survival. As of August 2009, 3756 HLA alleles have been identified, and the frequency distribution of HLA genes is characterized by significant population differences, so the chances of finding an identical HLA donor among unrelated individuals are very low. Despite the high polymorphism of HLA genes and population differences, many HLA antigen/allele differences are caused by individual or few nucleotide (amino acid) differences only, and many common epitope antigenic polypeptides exist between different HLA molecules, so immunogeneticists have proposed new mating strategies and theories such as amino acid residues, cross-reactive groups, acceptable mismatches, and amino acid sequence scoring. The so-called cross-reactive group refers to a group of different HLA molecules that cross-react with the same antibody because they have the same or similar antigenic determinant cluster structure or amino acid residues, and such a group of antigens is called cross-reactive group antigens (CREGs), and on this basis, cross-reactive group mapping and amino acid residue mapping strategies were proposed. Because different HLA molecules in the same cross-reactive group have the same or similar antigenic determinant cluster structure, the mismatch between them does not easily induce rejection, and the recipient can accept such mismatched antigen, so it is also called acceptable mismatched antigen (permissible mismatched antigen). In recent years, amino acid sequence scoring criteria have been proposed, i.e., the amino acid sequences of mismatched HLA alleles between donors and recipients are scored, and the best mismatched and acceptable mismatched antigen donors are selected according to their scores. As immunogeneticists continue to study HLA gene and molecular structure and function, and new donor-recipient mismatching strategies are proposed and applied, donor organs and tissues can be more scientifically and rationally allocated and effectively utilized, which is of great clinical importance to alleviate organ shortage, reduce clinical rejection, and improve transplantation success rate and long-term graft survival.