There is compelling evidence for the role of natural killer (NK) cells in tumor immunosurveillance and their beneficial effects on many experimentally successful immunotherapy strategies. NK cells mediate cell contact-dependent cellular cytotoxicity and produce pro-inflammatory cytokines, but do not rearrange antigen receptors. Their activation depends on various germline-encoded receptors, including CD16, which mediates recognition of antibody-coated target cells. NK cytotoxicity is checked by a repertoire of inhibitory receptors that scan adequate expression of major histocompatibility complex class I molecules on the potential target cell. Functional cross-talk of NK and dendritic cells suggests a critical role for NK cells in the initiation and regulation of cellular immunity. Considerable knowledge on the molecular basis of NK recognition/activation contrasts with a lack of successful translational research on these matters. However, there is plenty of opportunity for targeted intervention of inhibitory/activatory surface receptors and for adoptive cell therapy with autologous or allogeneic NK cells.