The signs and symptoms of persistent temporomandibular joint (TMJ)/muscle disorder (TMJD) pain suggest the existence of a central neural dysfunction or a problem of pain amplification. The etiology of chronic TMJD is not known; however, female sex hormones have been identified as significant risk factors. Converging lines of evidence indicate that the junctional region between the trigeminal subnucleus caudalis (Vc) and the upper cervical spinal cord, termed the Vc/C1-2 region, is the primary site for the synaptic integration of sensory input from TMJ nociceptors. In this paper, the mechanisms behind the estrogen effects on the processing of nociceptive inputs by neurons in the Vc/C1-2 region reported by human and animal studies are reviewed. The Vc/C1-2 region has direct connections to endogenous pain and autonomic control pathways, which are modified by estrogen status and are suggested to be critical for somatomotor and autonomic reflex responses of TMJ-related sensory signals.