Graft-mediated antileukemia (GVL) activity is a major factor contributing to the success of allogeneic hematopoietic stem transplantation (aHCT). Recent advances have permitted the establishment of GVL activity without the need for a myeloablative conditioning regimen, thereby permitting even older and sicker patients to avail of potentially curative therapy. Use of adoptive immunotherapy by combining reduced intensity conditioning and donor leukocyte infusion (DLI) has resulted in strategies that can be exploited to maximize GVL effects while minimizing toxicity. These advances, combined with new molecularly targeted agents, creates new possibilities to develop less toxic, curative therapy for a greater number of patients. This review summarizes pertinent information regarding the evidence in favor of GVL effects, the impact of disease type and mechanisms of GVL.