MHC class-1-specific inhibitory receptors were originally described in NK cells, in which they represent an important fail-safe mechanism that induces NK cell tolerance to normal self cells. These inhibitory NK receptors (iNKRs) were subsequently found expressed on different T cell subsets, primarily CD8(+) cytolytic T lymphocytes (CTLs), in which they can inhibit T cell receptor mediated functions. Some iNKR(+) CTLs are HLA-E-restricted, represent oligo- or monoclonal expansions, and can play a defensive role in viral infections. Although T cell activation, in the presence of certain cytokines, can induce the expression of the CD94-NKG2A heterodimeric receptor, the mechanism leading to the expression of killer immunoglobulin-like receptors (KIRs) is still unknown. The expression of iNKRs in T cells might contribute to the prevention of apoptotic cell death, thus allowing their survival and clonal expansion in vivo. In addition, iNKR(+) T cells might contribute to peripheral self-tolerance.