Tolerance of natural killer (NK) cells toward normal cells is mediated through their expression of inhibitory receptors that detect the normal expression of self in the form of class I major histocompatibility complex (MHC-I) molecules on target cells. These MHC-I-binding inhibitory receptors recruit tyrosine phosphatases, which are believed to counteract activating receptor-stimulated tyrosine kinases. The perpetual balance between signals derived from inhibitory and activating receptors controls NK cell responsiveness and provides an interesting paradigm of signaling cross talk. This review summarizes our knowledge of the intracellular mechanisms by which cell surface receptors influence biological responses by NK cells. Special emphasis focuses on the dynamic signaling events at the NK immune synapse and the unique signaling characteristics of specific receptors, such as NKG2D, 2B4, and KIR2DL4.