The molecules of the human leukocyte antigen (HLA) system play a central role in immunity, serving as the antigen presentation molecules recognized by T cell receptor. The large degree of polymorphism within the molecules of HLA system, and their counterparts in other species, provide individuals with large responsive repertoire to signal any potential invading agent or altered self-molecule to T cells. However, in transplantation, having different variants of these molecules within the population is counterproductive. The molecules of HLA systems are the triggers of alloreactivity leading to establishment of transplant rejection and the potential destruction of the transplant. In solid organ transplantation, recipient individuals tend to respond immunologically to differences in the antigenic composition of the donor HLA molecules, and the assessment of the degree of antigenic mismatch between donor and recipient can serve as a surrogate measurement of the risk for transplant rejection and eventual transplant loss. While waiting for the development of newer more efficacious and safer immunotherapies, achieving the best possible match or the less deleterious mismatch between donors and recipients appear to be a sensible strategy.