Graft-versus-tumor (GVT) reactivity mediated by donor T cells in the context of allogeneic stem cell transplantation (alloSCT) is one of the most potent forms of cellular immunotherapy. The antitumor effect against hematologic malignancies is mediated by a polyclonal T-cell response targeting polymorphic antigens expressed on hematopoietic tissues of the recipient, leaving donor hematopoiesis in the patient after transplantation unharmed. Fortunately, hematopoietic tissues (including malignant hematopoietic cell populations) are relatively susceptible to T-cell recognition. If, however, nonhematopoietic tissues of the recipient are targeted as well, graft-versus-host disease (GVHD) will occur. The balance between GVT and GVHD is influenced by the genetic disparity between donor and recipient, the number and origin of professional antigen-presenting cells provoking the immune response, the target antigen specificity, magnitude and diversity of the response, and the in vivo inflammatory environment, whereas inhibitory factors may silence the immune response. Manipulation of each of these factors will determine the balance between GVT and GVHD.