Natural killer (NK) cells are innate lymphocytes that control tumor progression by not only directly killing cancer cells, but also by regulating other immune cells, helping to orchestrate a coordinated anti-tumor response. However, despite the tremendous potential that this cell type has, the clinical results obtained from diverse NK cell-based immunotherapeutic strategies have been, until recent years, rather modest. The intrinsic regulatory mechanisms that are involved in the control of their activation as well as the multiple mechanisms that tumor cells have developed to escape NK cell-mediated cytotoxicity likely account for the unsatisfactory clinical outcomes. The current approaches to improve long-term NK cell function are centered on modulating different molecules involved in both the activation and inhibition of NK cells, and the latest data seems to advocate for combining strategies that target multiple aspects of NK cell regulation. In this review, we summarize the different strategies (such as engineered NK cells, CAR-NK, NK cell immune engagers) that are currently being used to take advantage of this potent and complex immune cell.