The intrinsic anti‐leukemic effect of allogeneic hematopoietic cell transplantation (HCT) is dependent on genetic disparity between donor and recipient, intimately associated with graft‐versus‐host disease (GVHD), and mediated by lymphocytes contained in or derived from the donor hematopoietic cell graft. Three decades of intense effort have not identified clinical strategies that can reliably separate the graft‐versus‐leukemia (GVL) effect from the alloimmune reaction that drives clinical GVHD. For patients who require HCT and for whom two or more human leukocyte antigen (HLA)‐A, ‐B, ‐C, and ‐DRB1‐matched donor candidates can be identified, consideration of donor and recipient genotype at additional genetic loci both within and outside the major histocompatibility complex may offer the possibility of selecting the donor [candidate(s)] that poses the lowest probability of GVHD and the highest probability of a potent GVL effect. Strategies for engineering conventional donor lymphocyte infusion also hold promise for prevention or improved treatment of post‐transplant relapse. The brightest prospects for selectively enhancing the anti‐leukemic efficacy of allogeneic HCT, however, are likely to be interventions that are designed to enhance specific antitumor immunity via vaccination or adoptive cell transfer, rather than those that attempt to exploit donor alloreactivity against the host. Adoptive transfer of donor‐derived T cells genetically modified for tumor‐specific reactivity, in particular, has the potential to transform the practice of allogeneic HCT by selectively enhancing antitumor immunity without causing GVHD.