Recently, donor lymphocyte infusions have been successfully used to treat patients with CML who have relapsed following allogeneic bone marrow transplantation (BMT). Responses can be achieved in more than 60-70% of patients with stable phase CML without the need for the additional high dose cytotoxic chemotherapy that would accompany a second transplant procedure. The clinical and molecular remissions induced by this approach are a clear demonstration of graft-versus-leukemia (GVL) activity. Although undoubtedly donor lymphocyte infusions are safer than a second BMT, they are associated with toxicities stemming from graft-versus-host disease (GVHD) and pancytopenia. In this review, the immunomodulatory mechanisms underlying the GVL activity of donor allogeneic lymphocytes infusions are presented. Unresolved issues regarding lymphocyte administration are discussed as well as potential ways to limit complications due to GVHD and pancytopenia. New potential applications of this immunotherapeutic approach for treatment of infectious disease and non-hematologic malignancies will be presented.