This paper reviews recent research that has provided important insights into the peripheral processes by which noxious stimuli activate or modulate nociceptive afferent inputs into the brainstem, that has identified the critical neural elements and pathways in the brainstem and higher levels of the trigeminal (V) somatosensory system that receive and transmit nociceptive inputs from orofacial tissues, and that has clarified some of the mechanisms involved in the modulation and plasticity of nociceptive transmission. The paper also outlines some of the clinical correlates of these research advances.