This article has discussed the peripheral and central mechanisms of the various orofacial pain conditions, including musculoskeletal disorders, neurogenic inflammation, and neuropathic pain. To make an accurate diagnosis of orofacial pain and render treatment, all organ systems need to be considered and evaluated. Central sensitization was discussed as it relates to musculoskeletal disorders and neuropathic pain. It has been suggested that treatment of these disorders be problem oriented, addressing both peripheral and central mechanisms if present. Musculoskeletal disorders are characterized by pain that is provokable with function and manipulation. Neurovascular pain is episodic with pain-free periods between attacks. The pain is not related to or provoked by jaw function. Neuropathic pain is more continuous and may be aggravated by light touch. Neuropathy with peripheral involvement responds variably to local anesthetics but may need to be treated with topical or local agents as well as centrally acting agents. Neuropathic pain that does not respond to topical or local agents is more profoundly centralized. These conditions need to be treated with centrally acting agents. In addition, if there is no response to medications, sympathetic involvement needs to be ruled out with sympathetic ganglion blockade.