MHC genes evolve through duplication, followed by diversification, co‐evolution, and sequence exchange. The focus, for HLA in transplantation, has been the specific classical class I and class II human leukocyte antigen (HLA) molecules and alleles. Importantly, anti‐HLA antibodies developed after the organ transplants play a role in acute and chronic allograft rejection, highlighting the need to detect these antibodies in a clinically relevant manner. Although the immune response to HLA antigens plays a pivotal role in allograft rejection, evidence shows that non‐HLA antigens also contribute to the pathogenesis of acute and chronic rejection, which limits long‐term graft survival of the solid organ transplants.