Natural killer (NK) cells are unique lymphocytes capable of lysing target cells without prior immunization. NK cells activated with cytokines, like interleukin-2 (IL-2), have been used since the 1980s as adoptive immunotherapy against metastatic solid tumors, but their effectiveness has been limited. The mechanisms by which NK cells recognize their targets are complex, including newly identified receptors that recognize class I MHC molecules. Understanding these mechanisms may support the use of NK cells as clinical therapy against infectious diseases and cancer. We have been interested in the use of NK cells clinically for their potential to eradicate minimal residual disease and prevent relapses after autologous stem cell transplantation. Several strategies are discussed to increase the specificity and efficacy of NK cell therapy. One method is to increase the targeting of NK cells by the use of monoclonal antibodies. Another approach uses allogeneic NK cells to overcome the inhibitory receptor mechanisms that may block target cell lysis by recognition of class I molecules. These and other novel strategies may prove to be attractive and effective immunotherapeutic tools to manipulate NK cells to fight human disease.