Recent studies have shown that NK cells recognize HLA-class I molecules. Moreover, the analysis of NK cell clones has provided evidence that they are capable of discriminating between different groups of HLA alleles. HLA class I recognition generates a negative signal which inhibits the NK cell cytotoxicity, thus resulting in target cell protection. HLA-class I recognition is mediated by clonally distributed receptors, some of which have been identified, characterized and cloned. The first two identified receptors were shown to be specific for HLA-C alleles, each recognizing a group of alleles sharing two amino acidic positions (77 and 80) in the peptide binding groove. The HLA-C specific receptors are represented by two 58 Kd (p58) molecules that are highly homologous, as shown by both biochemical analysis and by the comparison of the corresponding genes. Two additional receptors have been recently identified, which recognize two distinct groups of HLA-B alleles. These receptors are represented by the CD94 and by the NKB1 molecules, recognizing the Bw6 and Bw4 supertypic specificities. Recent analysis of the surface receptors involved in NK cell triggering has provided evidence that class I specific NK receptors can, in some instances, induce NK cell triggering, thus contributing to the activatory pathway of NK cells.