Donor lymphocyte infusion (DLI), which is therapy typically used after stem cell transplant, is a relatively new therapeutic intervention. It has been used in a number of hematopoietic malignancies, for some solid tumor malignancies, for its viral modulation effects, and as a prophylactic approach in the prevention of recurrent disease. The efficacy of this therapy is most evident in patients who have chronic myelogenous leukemia. However, studies of other diseases have been less forthcoming in showing clear benefit. Even in patient groups in which disease remission has been attributed to DLI, the risks of the treatment, namely graft-versus-host disease, may invalidate its use. This article summarizes a number of key studies addressing its usefulness in a number of disease states, risks of therapy, and strategies to ameliorate those risks while preserving benefit. It also examines tools that have been developed to more accurately describe survival benefits attributable to DLI.