Harnessing the host’s immune cells to recognize and eliminate cancer cells is a new paradigm in cancer therapeutics. Immunotherapy is now the way forward in combating all types of cancers, but cancer immunotherapies traditionally focus on the adaptive immune system. The strategies involved are checkpoint inhibitors and T-cell therapies, which work primarily on the adaptive arm of immunity. Recent discoveries indicate that new strategies can be developed if the cells of the innate immune arm are explored. Innate immune cells include natural killer (NK) cells, macrophages, dendritic cells, and neutrophils that act as the first line of defense against transformed cells. NK cells display strong cytotoxic activity without the need for antigen presentation and can kill tumor cells that are otherwise not targeted by T cells. Macrophages, especially tumor-associated macrophages (TAMs), can be polarized to an antitumor (M1) phenotype to neutralize their pro-tumorigenic (M2) phenotype in the tumor microenvironment. Dendritic cells bridge innate and adaptive immunity through the presentation of tumor antigens, while neutrophils can be reprogrammed to improve antitumor activity. In this chapter, we discussed how therapeutic strategies exploiting innate immunity include NK cell-based therapies and how macrophage reprogramming can stimulate innate immune activation. Innate immune memory, or “trained immunity,” also presents a promising avenue for sustained antitumor responses. Combining innate immune activation with adaptive approaches may synergistically enhance efficacy, overcoming resistance to monotherapies. The critical importance of developing new, integrative anticancer therapies relies on better understanding of the dual role innate immunity plays in tumorigenesis and tumour regression. Innate immune modulation represents an unused reservoir that may be focused to shift the therapeutic boundary from adaptive immunity.