Transplants from partially human leukocyte antigens (HLA)-incompatible relatives are associated with an increased risk of graft rejection, graft-versus-host disease (GVHD), and lower survival, which are correlated with the degree of disparity. For patients without an HLA-matched sibling, the preferred donors of hematopoietic cells remain HLA-compatible, unrelated volunteers. The hurdle for a wider application of hematopoietic cell transplantation is the enormous polymorphism of HLA genes that makes unrelated individuals unlikely to match randomly. The identification of functional HLA genes and their polymorphic alleles, the development of precise and effective tissue typing techniques, and the assembly of large volunteer registries worldwide that exceed 9 million HLA-typed individuals have made it feasible to transplant hematopoietic stem cells from well-matched, unrelated donors for most patients.