An understanding of the pathophysiology of pain involves the concepts of neuronal plasticity at the levels of the nociceptor neurons, spinal cord, and brain. Neuroplasticity allows the neurons in the brain to compensate for injury and adjust their activity in response to new situations or changes in their environment. This is an important physiologic event in the development of central sensitization. Other concepts include modulatory effects at the nociceptor, sympathetically mediated pain, the "wind-up" phenomenon, central sensitization, and descending and ascending central modulatory mechanisms for the perception of pain, as well as the related pain motivations and behaviors. Numerous modulatory mechanisms for pain have been postulated that control the degree of pain perceived and the emotional and behavioral phenomena associated with a patient's pain experience. These numerous mechanisms take place at all levels of the nervous system: peripheral nerves, spinal cord, and brain. Despite great advances in unraveling the complexities of the pathophysiology of pain, much remains to be discovered. It is hoped that further research into this critical area will lead to better therapies.