Natural cytotoxic effector functions are regulated by a multitude of opposing signals provided by immunoglobulin and lectin-like functional molecules. While inhibitory receptors possess ITIM cytoplasmic sequences recruiting tyrosine phosphatases, activatory receptors require association with accessory ITAM-bearing molecules. One considerable group of natural cytotoxic cell receptors are specific for classical and non-classical class I antigens and detect both qualitative and quantitative changes in the autologous MHC-I phenotype. Non-MHC-I specific receptors provide signaling in the absence of MHC-I antigens or in response to not well-known stress-induced antigens. NK cell receptors may equally participate in the regulation of target cell functions through contact or soluble mediator-dependent mechanisms. The identification of NK cell-regulating molecules has lead to the elucidation of more general principles underlying immune homeostasis.