Temporomandibular disorder (TMD) is a collective symptoms characterized primarily by persistent pain and functional disturbances. Pain from the temporomandibular joint (TMJ) is a major symptom of TMD. Although various pathologies within TMJ such as inflammation or degeneration can contribute to the persistent pain, the therapeutic management of such conditions is often not effective and so it is necessary to develop novel mechanism-based approaches to effectively treat the persistent pain conditions. It is well known that TMD is multifactorial condition and both peripheral as well as central mechanisms are intricately involved. It is important to identify local and systemic factors that contribute to persistent pain. Endogenous pain modulatory system and sex differences in painful TMD are also an important factors. This symposium will outline recently identified novel findings of the neural, molecular and neuro-endocrinological mechanisms underlying TMJ pain in rodent models and their implications for diagnosis and novel management of TMD.