The past ten years have witnessed dramatic progress in our understanding of how natural killer (NK) cells function, their role in innate defenses and their possible exploitation in therapy. This article traces the major advances in these formerly mysterious cells, from the 'missing self' hypothesis and the first discovery of HLA-class I-specific inhibitory receptors to a recent major breakthrough that highlighted important perspectives and major expectations regarding the cure of life-threatening leukemias. The key role of 'alloreactive' NK cells in eradicating acute myeloid leukemias and in preventing both graft rejection and graft-versus-host disease, might lead to a true revolution in bone marrow transplantation. Thus, it might now be possible to search for appropriate HLA class I mismatches to set NK cells in action.