In allo-HSCT, donor-derived, "alloreactive" NK cells have been shown to play a crucial role in the treatment of acute leukemia, contributing to eradication of leukemic blasts (GvL effect) and to clearance of residual recipient DCs and T lymphocytes (thus, preventing GvHD and graft rejection, respectively). Such alloreactive NK cells do not express CD94/NKG2A but express inhibitory KIRs, specific for HLA class I allotypes, present in the donor but lacking in the recipient. This review is focused on the role of the activating KIR2DS1 receptor (specific for the C2-epitope of HLA-C) in haplo-HSCT. Recent data indicate that KIR2DS1 expression in HSC donors may represent a remarkable advantage in alloreactive NK responses. This is a result of a substantial increase in the NK-mediated capability to kill, not only recipients' leukemic cells but also DCs and T cell blasts. The beneficial effects mediated by alloreactive KIR2DS1(+) NK cells may occur after de novo expression of CCR7 upon interaction with allogeneic, KIR ligand-mismatched CCR7(+) cells. As a consequence, they can be redirected to LNs, where they can prevent priming of donor T cells and induction of GvHD. Finally, KIR2DS1 expression may also significantly amplify the size of the alloreactive NK cell subset by switching a subset of "not alloreactive" NK cells into potent alloreactive cells.