The process of antibody-dependent cell-mediated cytotoxicity (ADCC) makes use of the innate immune cells providing antitumor cytotoxicity activated by antibodies linked to target cells. Natural killer (NK) cells are a small set of lymphocytes, but are considered the most important cells among those able to induce ADCC. They provoke innate immune responses and harmonise spontaneous cytotoxicity towards tumor and virus-infected cells. They are able to swiftly produce biochemical signals and cytokines so as to stimulate subsequent adaptive immune responses. Immunotherapeutics that target NK cells, augmenting their immune response, can cause the antitumor dynamics of the antibodies to be improved. The recent developments in the field of NK cell immunotherapy and genotypic factors which might affect patient responses to antibody-dependent immunotherapies are the main subject of this review, with a particular focus on the manipulations and strategies used to augment ADCC. In the next years combined treatment with monoclonal antibodies (mAbs) and immunomodulatory drugs will be an important part in antitumor therapy. The main challenge remains the difficulty in distinguishing in the clinical setting, between the target effect that many mAbs exert against specific cell membrane receptors and the ADCC effect that they too also can induce. Drugs able to activate NK cells, that are major actors in mAb-mediated ADCC, will improve the ADCC effect against tumors.