A multigene family of immunoglobulin superfamily (Ig‐SF) killer cell inhibitory receptors (KIRs) specifically recognize HLA class I molecules, while the interaction with H‐2 products is mediated by members of the murine Ly49 C‐type lectin family. A common structural feature of these receptors with inhibitory function is the presence of cytoplasmic immunoreceptor tyrosine‐based inhibitory motifs (ITIMs) that couple them to SHP phosphatases. Strong support for the involvement of the CD94 C‐type lectin receptor complex in NK cell‐mediated recognition of Bw6+ HLA‐B, HLA A and HLA‐C alleles has been obtained. The cloned CD94 molecule covalently assembles with at least two different glyco‐proteins (43 kDa and 39 kDa) to form functional receptors. NK cells inhibited upon HLA recognition express the CD94/p43 dimer, whose specificity for HLA molecules partially overlaps the Ig‐SF receptor system. By contrast. NK clones bearing the homologous CD94/p39 receptor are triggered upon its ligation by CD94‐specific mAbs. Remarkably, a set of Ig‐SF receptors (p50) homologous to p58 KIRs also display an activating function. CD94‐associated molecules belong to the NKG2 family of C‐type lectins; the NKG2‐A gene encodes for the p43 subunit. which contains cytoplasmic ITIMS. Expression of the different CD94 heterodimeric receptors will enable precise analysis of their putative interaction with HLA class I molecules.