The group of genes termed V-Set and Immunoglobulin (Ig) domain containing (VSIG) were originally identified as members of the large Ig superfamily. As more becomes known, they are increasingly recognized for their associations with other protein families. For instance, VSIG-1 is a member of the junctional adhesion molecule (JAM) family, while TIGIT/VSIG-9 and VSIG-4 contain structural similarities to the B7 family of immunomodulatory proteins. TIGIT/VSIG-9 plays essential roles in regulating T-cell and NK-cell subsets and VSIG-4 negatively regulates T cells. In addition, VSIG-3 is a putative ligand for the B7 family member Vista and inhibits T cell activation, making several members of the VSIG group immunotherapy targets.