Hematopoietic cell transplantation (HCT) from unrelated donors is a curative therapy for many malignant and nonmalignant blood disorders. The success of unrelated HCT is influenced by the degree of human leukocyte antigen (HLA) compatibility between the donor and patient. When donor matching for HLA alleles is feasible, overall transplant outcome is superior. The presence of donor-recipient mismatching is associated with increased risk of post-transplant complications including graft rejection, acute and chronic graft-versus-host disease (GVHD), and mortality; these risks are increased with multiple HLA mismatches. For the majority of patients who lack HLA-matched unrelated donors, current research is focused on the identification of permissible HLA mismatches. The influence of nongenetic factors on the tolerability of HLA mismatching has recently become evident, demonstrating a need for the integration of both genetic and nongenetic variables in donor selection.