NK cells play an important role in microbial host defense through direct cytotoxicity that kills pathogens. An ever-expanding list of fungi, bacteria, and parasitic organisms are susceptible to NK cell cytotoxicity. The receptors NK cells use and the pathogenic ligands recognized by NK cells are best defined for fungal pathogens. The downstream signal transduction pathways differ from those used by NK cells to kill tumor cells, and insights into the mechanisms of cytotoxic granule trafficking to fungi are complex and only beginning to be elucidated. NK cells use known cytotoxic proteins to kill pathogens, but the microbial pathways leading to cell death are largely unknown. Cytotoxic proteins are used in combination to kill microbes, although the permutation depends on the specific pathogen. In this review, we will describe what is known about the receptors, signaling, granule trafficking, and effector proteins used by NK cells to kill fungi.