Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for a range of malignant and non-malignant diseases. Unfortunately, fewer than 30% of patients have a human leukocyte antigen (HLA)-matched sibling. Advances in our understanding of the HLA system and the development of large international donor registries are supporting the increasing use of unrelated donors as an alternative source of stem cells. Unrelated donor transplantation, however, is still associated with higher complication rates than in HLA-identical sibling donor transplants. Improvements in graft-vs.-host disease prevention and treatment, new conditioning regimens and better donor selection will likely expand the indications of unrelated donor HSCT in the next decade.