Natural killer (NK) lymphocytes are powerful effector cells of the peripheral immune system. NK cell functions are controlled by the expression of a variety of cell surface receptors with either inhibitory or activating roles. The genetic and functional diversity of this repertoire of receptors and the role of human leukocyte antigen class I histocompatibility molecules as a major group of NK receptor ligands endows NK cells with an innate alloreactive capacity. Early studies of experimental bone marrow transplantation revealed an important role for NK cells in the rejection of allogeneic grafts and contributed significantly to our understanding of NK cell behavior. Both animal models and in vitro studies have since implicated NK cells as contributors to the pathology of clinical transplantation. However, recent clinical studies have demonstrated the potential benefits of exploiting NK cell alloreactivity in mismatched hematopoietic stem cell transplantation for particular types of acute leukemia. Future investigations of NK cell alloreactive functions will undoubtedly reveal additional roles and potential therapeutic applications of this fundamental cell type in clinical transplantation.