For decades, the driving force behind many immunologic studies has been the hope of augmenting anti-cancer therapy through targeted immune-based strategies. The question remains: can immune cells be successfully manipulated to augment chemotherapy and aid in the elimination of malignancy? Such efforts have included work with natural killer (NK) cells, large granular lymphocytes that contribute to the early innate immune response by nonspecifically killing pathogens, virus-infected cells, and tumor cells, and by producing important early immunoregulatory cytokines such as interferon gamma (IFN-gamma). These qualities have made NK cells attractive candidates for therapy aimed at boosting host immunity against tumor cells and infectious pathogens. Recent advances in our understanding of how NK cells select targets for killing have improved our ability to design and test more effective immune-targeted therapies. However, our understanding of NK leukemias and lymphomas remains incomplete. NK leukemias and lymphomas, while rare, represent a significant challenge to the patients and physicians coping with them, as most lack effective treatment strategies. This brief review will summarize current directions in NK cell immune therapy and give an update on the classification and treatment of NK malignancies.