 Immuno-oncology has revolutionized cancer patient care by harnessing the power of the adaptive immune response through therapeutic targeting of T cells. However, this approach does not work for all patients or tumor types, leading researchers to explore alternative strategies. One such strategy involves engaging the innate immune system, specifically natural killer, NK cells. This review discusses how targeting NK cells can be used to treat cancer, focusing on two key activating receptors, NK group 2D, NKG2D, and cluster of differentiation 16A, CD16A, which are involved in the activation of NK cells. This article was authored by Kerry A. Waylon, Kovya Rockra, Naveen K. Mehta, and others.