The generation of neuropathic pain is a complex phenomenon involving a process of peripheral and central sensitization producing enhanced transmission of nociceptive inputs to the brain associated with the loss of discriminatory processing of noxious and innocuous stimuli. This increased flow of abnormally processed nociceptive inputs to the brain may overcome the ability of descending modulatory pathways to produce analgesia, causing further worsening of the pain. Several crucial locations involved in the physiologic generation of pain inputs (eg, peripheral nociceptors, dorsal horns, thalamus, cortex) show evidence of functional reorganization and altered nociceptive processing in association with chronic pain. These locations present the best targets for therapeutic intervention, including systemic administration of drugs able to counteract the chemical storm induced by neural injuries in the nociceptive afferents and dorsal horns, or for more focused intervention, such as neuroablative procedures; intrathecal drug delivery; and spinal cord, deep brain, or motor cortex stimulation.