Natural killer (NK) cells of the innate immune system are the first line of defense against infectious agents and cancer cells. However, only a few mechanisms that regulate eradication of tumors by NK cells have been identified. In this review, we present an account of epigenetic mechanisms that modulate the ability of NK cells to eradicate cancer cells. To date, several drugs that target epigenetic modifiers have shown clinical efficacy in cancer. Therefore, once a given epigenetic modifier is validated as a regulator of NK cell function, it can be targeted for NK cell-based cancer immunotherapies.