Pain is both a sensory event of the peripheral and central nervous systems and an experience that arises from, and reciprocally can affect processes of higher consciousness. Alterations in peripheral and central neuraxes can lead to sensitization, structural modification and long-term potentiation that can overcome modulatory influence(s) and change the non-linear adaptability of these systems to a progressively linear, pathologic state with a diverse constellation of clinical signs and symptoms. Recent progress in molecular biology, neurochemistry and neuroanatomy has led to significant advancement in understanding the interactive roles of these heterogeneous systems in mediating and modulating various types of pain. This review concisely provides an overview of the structure and function of these substrates. As we reach the midpoint in a decade marked by pain control and research, such knowledge is critical to further both a more comprehensive appreciation of the phenomenon that is pain, and the development of therapeutic interventions that are innovative and effective.