This article presents an overview of possible mechanisms associated with pain perception, with a specific focus on understanding unusual manifestations of orofacial pain associated with nerve insult. It includes recent evidence concerning neurobiological changes that occur in the periphery at tissue and nerve sites, or within the central nervous system, and that may involve chemical and inflammatory responses, sensitization, or alterations of cellular function. Moreover, the contribution of the autonomic nervous system, changes in emotional reactivity and vigilance, the roles of high brain centers such as the basal ganglia (nigro-striatal) system, and the influence of aging and gender, are briefly described.