Natural killer (NK) cells are large granular innate lymphocytes crucial for the early control of oncogenic transformation and viral infections. Although initially defined as common cytotoxic cells, we know now that they use a sophisticated repertoire of germline-encoded activating and inhibitory receptors finely regulated to ensure self-tolerance while eliminating cancerous cells. Specific self-recognition of human leukocyte antigen class I (HLA-I) by killer cell immunoglobulin-like receptors (KIR) is crucial for human NK cell development and function. This allows NK cells to recognize and kill cancerous cells that have lost HLA-I molecules to escape T cell responses while keeping healthy cells unharmed. KIR and HLA genes are highly polymorphic, and their independent segregation produces a high diversity in the number and type of KIR-HLA combinations. In this sense, interindividual differences in the KIR-HLA constellation may influence clinical outcomes in diverse settings, including cancer, infections, autoimmune diseases, fertility, and transplant rejection. The attractive features of NK cells, such as HLA-independent antigen recognition, rapid killing ability, and enhancement of B and T cell responses, point toward NK cells as attractive “living therapeutics.” In this sense, the adoptive transfer of ex vivo activated, ex vivo expanded, and genetically modified NK cells (CAR-NK) and the pharmacological targeting of their immune checkpoint inhibitors have shown promising antitumoral effects. This chapter reviews the recent advances in using NK cells for cancer immunotherapy and discusses the role of host immunogenetics in the efficacy of antitumoral NK cell therapies.