Natural killer (NK) lymphocytes are potent effector cells that are controlled by the expression of a variety of cell surface receptors with either inhibitory or activating functions. The genetic and functional diversity of this receptor repertoire and the role of HLA class I molecules as a major group of NK receptor ligands create an innate alloreactive capacity in this cell type. Both animal models and in vitro studies have implicated NK cells as contributors to the pathology of clinical transplantation. However, recent clinical studies have indicated the potential benefit of exploiting NK cell alloreactivity in mismatched haematopoietic stem cell transplantation. Further investigations of NK cell alloreactivity will undoubtedly reveal additional applications of this fundamental cell type in clinical transplantation.