Donor T cells present within hematopoietic stem cell transplants promote engraftment, contribute to T-cell reconstitution and provide an antileukemic effect. However, they are also responsible for the life-threatening graft-versus-host disease. The subpopulation of CD4⁺CD25^hi regulatory T cells, initially identified as crucial players in the regulation of autoimmune processes, might also play a role in the control of alloreactivity. Experimental studies in mice indicate that donor regulatory T cells indeed control alloreactive responses and reduce graft-versus-host disease. Recent clinical reports also suggest that higher numbers of CD4⁺CD25^hi cells within the transplant or in the blood of grafted patients might be associated with reduced graft-versus-host disease. Hence, these cells are attractive immunoregulatory candidates to prevent graft-versus-host disease in humans.