Antibody-dependent cellular cytotoxicity (ADCC) is a set of mechanisms that target cells coated with IgG antibodies of the proper subclasses (IgG1 in the human) to be the prey of cell-to-cell cytolysis executed by immune cells expressing FcRIIIA (CD16A). These effectors include not only natural killer (NK) cells but also other CD16+ subsets such as monocyte/macrophages, NKT cells or γδ T cells. In cancer therapy, ADCC is exploited by antibodies that selectively recognize proteins on the surface of malignant cells. An approach to enhance antitumor activity is to act on effector cells so they are increased in their numbers or enhanced in their individual (on a cell per cell basis) ADCC performance. This enhancement can be therapeutically attained by cytokines (that is, interleukin (IL)-15, IL-21, IL-18, IL-2); immunostimulatory monoclonal antibodies (that is, anti-CD137, anti-CD96, anti-TIGIT, anti-KIR, anti-PD-1); TLR agonists or by adoptive infusions of ex vivo expanded NK cells which can be genetically engineered to become more efficient effectors. In conjunction with approaches optimizing IgG1 Fc affinity to CD16, acting on effector cells offers hope to achieve synergistic immunotherapy strategies.