The natural killer (NK) cell effector response towards infected cells or tumoural cells is guided by the integration of activating and inhibitory signals sensed by NK cell surface receptors. Major histocompatibility complex class I specific inhibitory receptors expressed by NK cells have two distinct roles: while allowing self tolerance, they are also needed for the acquisition of NK cell functional competence, a process termed education. In the context of allotransplantation, NK cell alloreactivity, arising from the expression on donor NK cells of inhibitory killer Ig-like receptors (KIRs) that do not recognize human leukocyte antigen from the patient, has shown clinical benefit for leukaemia patients. Based on these genetic studies, a blocking antibody directed against KIRs, as well as allogeneic NK cell infusions are now tested in clinical trials in various oncology indications. They offer promising immunotherapeutic approaches for the treatment of cancer patients.