Results of recent experiments have provided compelling evidence supporting the hypothesis that the acute rejection of bone marrow transplants by allogeneic and semiallogeneic recipients is principally due to the action of natural killer (NK) cells. The observed specificity of graft rejection is likely induced by target-specific antibody that guides the NK cells in an antibody-dependent cytolytic reaction resulting in the elimination of the graft. The sole involvement of NK cells in marrow graft rejection, however, is contradicted by several observations that point to the environment of specific T cells. Results presented in this paper demonstrate that in allogeneic marrow graft rejection models, T killer cells are capable of causing graft rejection provided a prior sensitization phase is allowed. Thus, mice not able to reject marrow grafts in a primary response via their NK cells will do so in a primed secondary response via their T cells. Rejection is specific in that only marrow grafts H-2 identical to the sensitizing marrow graft are rejected. Sensitization for NK cell independent marrow graft rejection can be accomplished by prior priming with allogeneic tumor cells or by injection of cloned T killer cells. In contrast to bone marrow allograft rejection, the hybrid resistance model in which F1 hybrid mice reject parental marrow grafts does not appear to induce T killer cells in vivo. Neither marrow grafts nor tumor cells prime F1 hybrids for a second-set parental graft rejection. Moreover, F1 hybrid antiparental T killer cells induced in vitro and adoptively transferred in vivo fail to transfer hybrid resistance. Therefore, there appear to be potent mechanisms acting in vivo that suppress the action or induction of F1 hybrid T killer cells specific to parental antigens.