NK-cell activity against tumor cells is regulated by a complex balance of inhibitory and activating signals, which are mediated by the binding of NK-cell receptors to activating and inhibitory ligands expressed on tumor cells. Thus, the disruption of the inhibitory cascade would shift the balance to activation. IPH-2101 (1-7F9), being developed by Innate Pharma, is a fully human IgG4 anti-killer immunoglobulin-like receptor (KIR) mAb for the treatment of hematological malignancies, such as acute myeloid leukemia (AML) and multiple myeloma (MM). In preclinical studies, IPH-2101 selectively bound to KIR2DL1, 2 and 3, and KIR2DS1 and 2, and exposure of KIR-transfected target cell lines to IPH-2101 led to an augmented NK-cell-mediated lysis. In phase I clinical trials in patients with AML and MM treated with IPH-2101, activation of NK cells was observed and IPH-2101 exhibited a good safety profile. At the time of publication, patients with MM had been recruited to phase II clinical trials to assess single-agent IPH-2101 or IPH-2101 in combination with lenalidomide. These and larger, randomized trials are warranted to clarify whether enhancing a patient's NK-cell activity by IPH-2101 will be a viable approach in the treatment of hematological malignancies.