Natural killer (NK) cells belong to the first line of defense and can directly recognize and eliminate cancer cells, but they also recruit and stimulate other immune components to further boost the anti-tumoral immune response. However, in the context of established tumors, NK cells are often dysfunctional or decreased in numbers. Multispecific NK cell-targeting antibodies, such as Innate Cell Engagers (ICE®) and other NK cell engagers, are a rapidly emerging technology in the field of targeted immuno-oncology therapies. They specifically redirect NK cells to the tumor and enhance their anti-tumor activity through simultaneous binding of innate immune cell receptors and tumor (associated/specific) antigens. Hence, innate immune cell engagers re-enable the patient’s own natural cellular armamentarium to fight cancer. The anti-tumor activity of agents that activate innate immunity has been demonstrated in numerous proof-of-concept studies using preclinical models. Furthermore, early-stage clinical studies of ICE® achieved groundbreaking success in selected cancer indications in combination with NK cell therapy, giving hope to patients that are refractory to multiple lines of treatment. In this chapter, we will describe current concepts to leverage innate immune cells and highlight their success stories and remaining challenges in clinical development.