TNFRSF9, also known as 4-1BB and CD137, is a member of the tumor necrosis factor receptor superfamily (TNFRSF). It is a costimulatory receptor similar to OX40, CD27, CD30, and CD40. The interaction of TNFRSF9 and its ligand, TNFSF9, leads to the activation of cytotoxic T cells, reactivation of anergic T lymphocytes, and induces T cell proliferation. TNFRSF9/TNFSF9 preferentially enhances the expansion of CD8+ T cells rather than CD4+ T cells, through the increase of IL-2Rα (CD25) and IL-2 expressions in CD8+ T cells. Among the TNFRSF members, TNFRSF9 is the most potent inducers of IL-2Rα expression on CD8+ T cells. In vivo studies with TNFSF9 knockout mice and with the agonistic anti-TNFRSF9 monoclonal antibody showed that TNFRSF9/TNFSF9 interaction keeps optimal CD8 T-cell mediated immune response against viral infections and tumors. The mouse TNFRSF9 has 60% identity to the human receptor at the amino acid level.