Natural killer (NK) cells possess potent cytolytic activity and secrete immune modulating cytokines. The large repertoire of NK cell receptors provides versatility for the identification of infected and transformed cells and for their elimination by NK cells. NK cell responses also stimulate and regulate the adaptive arm of the immune system. We review current knowledge about the molecular specificity of NK cell receptors and about the regulation of NK cell effector functions upon encounter with target cells. Mechanisms of recognition, interplay among receptors, signal integration, and the dynamic fine-tuning of NK cell responses are discussed. New insights into the molecular checkpoints for NK cell effector function are highlighted, and underlying reasons for the complexity in NK cell recognition and signaling are proposed.