The use of an HLA-compatible unrelated donor is an option for patients who require an allogeneic transplant but lack a family member match. Grafts from unrelated volunteer donors have provided long-term disease-free survival for a variable proportion of patients, depending on degree of HLA matching with the donor, patient's disease, disease stage, and age. The number of volunteers in marrow donor registries worldwide has increased to more than 2.5 million. The number of unrelated donor transplants facilitated by the US National Marrow Donor Program alone will exceed 900 this year. Progress in HLA-typing technology results in a more precise definition of donor and recipient matching and new assays have been developed with initial success to measure alloreactive T-cell precursors for selection of donors with less antihost reactivity. Prevention and treatment of graft failure, graft-versus-host disease, opportunistic infections, and Epstein-Barr virus-associated lymphoproliferative disease remain a challenge.