There are three main approaches currently being pursued to modulate the FGL2–FcγRIIB pathway for clinical benefit: (1) development of rFGL2 (monomeric and oligomeric) to inhibit immune responses; (2) expansion of TIGIT⁺ Treg expressing high levels of FGL2, which would represent a cellular therapy for transplantation and autoimmune disease; and (3) development of anti-FGL2 monoclonal antibodies to inhibit FGL2 signaling and enhance immune responses in cancer and chronic infections. DC, dendritic cell; PVR, poliovirus receptor; rFGL2, recombinant FGL2; TIGIT, T cell immunoreceptor with Ig and ITIM domains; Treg, regulatory T cell.