The use of human leukocyte antigen (HLA)-incompatible transplantations, in addition to cord blood transplantation, is rapidly increasing due to the development and refinement of graft-versus-host disease prophylactic treatment with post-transplant cyclophosphamide or anti-thymocyte globulin. However, caution must be observed in interpretating the significance of HLA incompatibility because each transplant source differs, which affect the association between HLA compatibility and transplant outcome. In addition, the loci that should be evaluated, the level of matching (antigen/allele), the direction of incompatibility (graft-versus-host or host-versus-graft), and the combination of incompatible HLA alleles must be understood. Notably, the significance of HLA incompatibility changes with the development and improvement of GVHD prophylactic treatment. Factors that should be prioritized in donor selection should be evaluated in the future. This article outlines the significance of HLA incompatibility in each transplant source.