Novel immune-type receptors (NITRs) are encoded by clusters of multigene families and have been identified in multiple bony fish species. All NITRs possess one extracellular immunoglobulin (Ig) domain of the variable (V) type and recent crystal structures of NITR V domains demonstrate their high degree of similarity to V domains of antigen receptors. Many NITRs possess a second extracellular Ig domain of the intermediate (I) type which helps differentiate NITRs from other V domain receptors. The majority of NITRs are type I transmembrane receptors; however, a small number are predicted to encode secreted proteins. Based on their sequence and structure, NITRs have been proposed to be "functional orthologs" of mammalian natural killer receptors (NKRs). Like NKRs, most NITRs possess short functional motifs permitting their classification as inhibitory or activating. NITRs lacking these motifs are functionally ambiguous. Inhibitory and activating NKRs utilize opposing signaling mechanisms to influence the response of NK cells to target cells; studies employing recombinant NITRs suggest that these signaling pathways are conserved between NKRs and NITRs. An analysis of all published NITR sequences demonstrates the conserved nature of multiple residues within the NITR Ig domains permitting the identification of NITR ESTs from salmon, cod, halibut, lake whitefish and stickleback species. Complete data sets of NITRs from the sequencing of the zebrafish and medaka genomes provide insight into the evolution of the NITRs within bony fish species. It is likely that all teleost species encode NITRs which function within innate immunity to regulate cell mediated cytotoxicity.