SummaryNatural killer (NK) cells are innate lymphocytes that react without previous exposition to virus infected or malignant cells and stimulate adaptive immune response to build a long-lasting immunity against it. To that end, tissue resident NK cells are predominantly regulatory as opposed to cytotoxic. In the hematopoietic stem cell transplant (HSCT) setting, which curative potential relies on the graft versus leukemia effect, NK cells are known to play a significant role. This knowledge has paved the way to the active investigation on its anti-tumor effect outside the stem cell transplant scenario. Based on the relevant literature on the adoptive transfer of non-genetically modified NK cells for the treatment of relapsed/refractory acute leukemia and on our own experience, we discuss the role of donor cell peripheral blood persistence and expansion and its lack of correlation with anti-leukemia activity.