Review of KIR2DS1 expression in HSC donors as a remarkable advantage in KIR/KIR‐ligand mismatched haplo‐HSCT. 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 recipientsˈ 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.