These experiments have investigated cellular mechanisms involved in the generation of cellular immune responses to human acute leukemic blasts. Because normal human lymphocytes are not able to recognize immunologically, in vitro, lymphocytes from MHC identical siblings, the present studies have examined the in vitro proliferative and cytotoxic responses of normal lymphocytes to MHC identical AML and ALL blasts. In those cases where acute leukemic cells were unable to induce a proliferative response by MHC identical lymphocytes, the generation of effective anti-leukemic cytotoxicity required the addition of unrelated stimulating cells to the sensitization culture. In contrast, leukemic blasts that induced a proliferative response by MHC identical lymphocytes were also able to stimulate anti-leukemic cytotoxicity. This could be augmented by the addition of unrelated stimulating cells to the sensitization culture. The specificity of anti-leukemic cell cytotoxicity was demonstrated in all instances by simultaneous testing of putative killer cells on 51Cr leukemic blasts as well as 51Cr-labeled MHC identical phytohemagglutinin blasts or normal lymphocytes. Simultaneous sensitization to MHC identical leukemic blasts and unrelated stimulating lymphocytes did not invariably generate anti-leukemic cytotoxicity even when allogeneic cytotoxicity was observed; the absence of demonstrable suppressor activity in these nonreactive combinations suggested that some individuals may be specifically immunoincompetent, and thereby unable to generate effective anti-leukemic CML.