Donor leukocyte infusion (DLI) is used after both myeloablative and non-myeloablative stem-cell transplantation to treat and prevent relapse, to establish full donor chimerism, and to treat and prevent infections. The major treatment-related complication of DLI is graft-versus-host disease (GVHD). The presentation and treatment of GVHD after DLI is similar to its presentation and treatment after stem-cell transplantation, with some notable exceptions. While GVHD and graft-versus-tumor (GVT) effects are highly correlated after DLI, some patients experience remission without GVHD. Studies to define tumor-specific target antigens and GVT effector cells, as well as strategies of donor T-cell manipulation and optimization of DLI dose and schedule, may ultimately lead to the consistent ability to separate GVHD from GVT activity, improvement in the safety and specificity of DLI, and enhancement of the anti-tumor activity of donor T cells.