In contrast to the well-established cytotoxicity of NK cells against AML cells, their capacity to lyse ALL cells is generally low and difficult to predict. We sought to overcome this intrinsic resistance by transducing CD56+ CD3─ NK cells with chimeric receptors directed against CD19, a molecule widely expressed by malignant B cells. Expression of anti-CD19 receptors linked to CD3zeta overcame NK resistance and markedly enhanced NK cell-mediated killing of leukemic cells. This result was significantly improved by adding the 4-1BB costimulatory molecule to the chimeric anti-CD19-CD3zeta receptor: the cytotoxicity produced by NK cells expressing this construct uniformly exceeded that of NK cells whose signaling receptors lacked 4-1BB, even when natural cytotoxicity was apparent (Imai et al., Blood 2005). NK cells expressing anti-CD19 receptors also exerted vigorous anti-ALL activity in a murine model of leukemia (Shimasaki et al., Cytotherapy 2012). Our findings indicate that enforced expression of signaling receptors by NK cells might circumvent inhibitory signals, providing a novel means to enhance the effectiveness of anti-ALL NK cell therapy.