Natural killer (NK) cells have been shown to play an important role in cancer, particularly hematologic malignancies. In contrast to T cells, NK cells are able to kill cancer cells without prior sensitization. They recognize the lack or alteration of self-MHC class I molecules as well the presence of stress ligands, both of which have been shown to be differentially altered in several cancers, making NK-based immunotherapy a plausible therapy against cancer as a single therapy or in combination with current cancer therapies. Some NK-based immunotherapies such as the adoptive transfer of activated allogeneic NK cells after hematopoietic stem cell transplantation (HSCT) in hematological malignancies have demonstrated promising outcomes. Moreover, differences in NK subsets are just starting to be elucidated which are leading to the optimization of therapies which selectively expand those NK cells that would elicit the greatest anti-tumor efficacy. In this review, we will summarize our current understanding of NK cell biology particularly as it relates to use in cancer therapy as well as assess the different mechanisms that tumor cells have evolved to evade NK cells. We will also summarize the NK-based therapies that have previously been applied in cancer, those that are currently under investigation, and possible future directions.