Current cancer immunotherapies have begun to target cell types involved in innate immunity, such as natural killer (NK) cells that recognize and kill tumor cells. Recent advances in the study of NK cell biology have generated interest in manipulating these cells to generate anti-tumor responses. A rise in the number of activated NK cells has been shown to prevent and treat cancer in many preclinical models and is a positive clinical factor in human tumors. This article will focus on recent research on the ability of IL-15 and Toll-like receptor ligands to stimulate NK cell activity against cancer. The potential of these therapies, both alone and in conjunction with traditional and other vaccine platforms, will be reviewed. The current status of these therapies in clinical trials will also be discussed. Targeting these cell types in the context of human cancers may be an essential factor in future cancer treatments.