HLA disparity between hematopoietic stem cell (HSC) donor and recipient triggers T-cell and NK-cell allorecognition, and induces the GVHD, GVL effect and/or may cause an engraftment failure. This review will cover the scope of human genomic variation, the methods of HLA typing and interpretation of high-resolution HLA results. We describe the main subsets of related and unrelated HSC donors and outline the main aspects of HLA disparity and their effect on the outcome of the patients after allogeneic HSC transplantation (HSCT). The HLA match between HSCT donor and recipient is crucial, but for many patients a perfectly matched donor is not available. The HSCT from the alternative mismatched donor with one allele/antigen mismatch (9/10) can be as beneficial as a HSCT from a fully matched donor, especially in younger patients. For the remaining patients, the donors with permissive mismatches may be the option. The permissiveness depends not only on the potential adverse effect of the HLA mismatches, but also on the urgency of the transplantation, the desirable GVL effect and the potential efficacy of the alternative therapy available for the patient.