Recent studies have identified cell surface molecules that appear to play important roles in natural killer cell specificity for their targets. Natural killer cells display activation 'receptors', such as NKR-P1 molecules in rodents, that may activate cytotoxicity by transducing biochemical signals. These molecules presumably interact with target cell surface ligands but these structures have not been elucidated. Natural killer cells display other molecules, such as Ly-49 in mice, that appear to be 'inhibitory' receptors that engage target cell MHC class I molecules and deliver signals, negatively regulating natural killer cell cytotoxic activity. The murine NKR-P1 and Ly-49 molecules are structurally similar and encoded by members of polymorphic gene families that reside in the natural killer gene complex on the distal region of mouse chromosome 6. Additional molecules have been serologically defined and studied functionally in murine and human systems. Thus, the specificity of an individual natural killer cell may be determined by its expressed repertoire of these molecules. The complexities of this recognition system are beginning to be appreciated at the molecular level.