Chronic pain has substantial effects on patients' quality of life and psychological well-being. It does not respond satisfactorily to available medicinal therapeutics because its mechanism remains unclear. Recent studies have shown a strong relationship between chronic pain and immunomodulation. As important members of the immune response, CD28 superfamily costimulatory molecules were demonstrated to have an analgesic effect on chronic pain. Based on research on the role of these molecules in chronic pain, new and highly effective analgesic medicines are anticipated that could be used in combination with some previous analgesic medicines to reduce substance abuse and side effects. This review of the literature will examine the pain-regulating mechanisms of CD28 superfamily costimulatory molecules, focusing on immunomodulation. In addition, this review will discuss the potential and difficulties of developing novel analgesic medicines targeting CD28 superfamily costimulatory molecules.