OX40 (CD134), a membrane-bound member of the tumor-necrosis-factor-receptor superfamily, is expressed primarily on activated CD4+ T cells. Recently, several groups have reduced clinical signs of autoimmunity in animal models by blocking the OX40-OX40-ligand interaction or depleting OX40+ T cells. By contrast, engagement of OX40 in the setting of active immunization has potent adjuvant properties, leading to enhanced cytokine production and increased numbers of antigen-specific memory T cells. These potent adjuvant effects lead to an enhancement of anti-tumor responses. OX40 has several unique features that make it a clinically relevant target. They include: (1) T cells isolated from a site of inflammation that express OX40 are T cells that have been stimulated recentlythrough the T-cell receptor in vivo; (2) OX40 is only expressed on T cells found at the site of inflammation, therefore, targeting this receptor does not interfere with the peripheral T-cell repertoire; and (3) the biological function of OX40 is limited primarily to effector CD4+ T cells, which are a major source of cytokines to induce and maintain ongoing immune responses.