Optimal T cell response is dependent not only on T cell receptor activation, but also on additional signaling from coreceptors. The main coreceptors include B7 and tumor necrosis factor family members. They exert costimulatory or coinhibitory effects, and their balance determines the fate of T cell response. In normal conditions, costimulators facilitate the development of protective immune response, whereas coinhibitors dampen inflammation to avoid organ/tissue damage from excessive immune reaction. In the tumor microenvironment, the balance is garbled: inhibitory pathways predominate, and T cell response is impaired. The importance of cosignaling in the tumor immune response has been experimentally and clinically demonstrated. New therapeutic strategies targeting T cell cosignaling, especially coinhibitory molecules, are under active experimental and clinical investigation. This review summarizes the functions of main T cell cosignaling axes and discusses their clinical application.