Unrelated-donor transplants have been a realistic option for an increasing number of patients, and the results of these transplants are favorable for patients with good prognostic features. Timing of the transplant early in the course of disease, before malignant clones become resistant to therapy and while the patient remains in good clinical condition, is a critical variable. Further improvements in the safety and efficacy of unrelated-donor transplants will require new approaches to GVHD prevention, better supportive care, acceleration of immune reconstitution and facilitation of tolerance induction without loss of the graft-versus-leukemia effect.