Efforts at harnessing the antitumour activity of natural killer (NK) cells have been investigated for the immunotherapy of human cancer for over two decades. Initial trials, focusing on the use of ex vivo-generated lymphokine activated killer (LAK) cells or activated NK cells, or in vivo cytokine therapy to expand and activate NK cells against autologous tumours, have yielded only modest success. Recent understanding of the means by which NK cells kill target cells through a complex set of activating and inhibitory receptors recognising corresponding ligands on tumour cells has paved the way for the design of improved strategies for NK cell-based immunotherapy. The net balance of activating and inhibitory signals through NK cell receptors determines whether an NK cell becomes activated or not. Successful therapeutic strategies should now focus on manipulating the balance in favour of activating receptor signalling. In the case of autologous cancers, such strategies may include the use of monoclonal antibodies with cytokines to better direct NK cells to their tumour targets through the process of antibody-dependent cellular cytotoxicity (ADCC) or the in vivo blocking of inhibitory interactions between NK receptors (NKRs) and ligands on tumour cells. Alternatively, allogeneic NK cells can be used whenever there is mismatching of inhibitory NK cell receptors and ligands. Finally, methods to modulate expression of NK cell receptors and their ligands on tumour cells by cytokines and other agents should be explored. In this review, the impact of NKR biology on the development of novel strategies for the use of NK cells in the treatment of human cancer is discussed.