Chronic pain is a major cause of suffering. This interferes with daily functioning and is often accompanied by distress. However, current therapeutic strategies for chronic pain are unsatisfactory because of poor understanding of its mechanisms. Therefore, more comprehensive therapeutic targets must be identified to improve the quality of life of these patients. Myeloid differentiation primary response protein 88 (MyD88) is an adaptor protein of the toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families. Recently, overexpression of MyD88 in the spinal and dorsal root ganglia was observed in multiple pain models, which also revealed that MyD88 plays an important role in the development and maintenance of chronic pain. In this review, we summarized the roles and mechanisms of MyD88 in the progression of different pain models, including chemotherapy-induced peripheral neuropathy (CIPN), diabetic neuropathic pain (DNP), spinal nerve ligation (SNL), chronic constriction injury (CCI), spinal cord injury (SCI) and inflammatory pain.