Tumor necrosis factor receptors (TNFR-) are emerging as an important class of pharmaceutical targets that have potential value for the treatment of numerous diseases, including cancer, inflammatory diseases, as well as autoimmune diseases. Although a lot of antibody reagents targeting TNFRs have entered clinical investigation, few of them have been approved for clinical use. More importantly, small-molecule TNFR- inhibitors have rarely entered clinical trials. This brief review focuses on the development of small molecular TNFR- modulators that have been reported in recent decades, with the aim of shedding light on the future discovery and application of more potent and promising small-molecule TNFR modulators.