Advances in the characterization of pain signaling in recent years indicate that distinct neurophysiological and neurochemical mechanisms contribute to pain arising from injury to the nervous system (neuropathic pain). Tissue injury results in the release of pro-nociceptive mediators that sensitize peripheral nerve terminals (peripheral sensitization), leading to neurochemical and phenotypic alterations of sensory neurons and increased excitability of spinal cord dorsal horn neurons (central sensitization). In addition, the response of the nervous system to pain is not static, but is modulated by descending systems originating in the brain that can modulate pain thresholds. In this review, attention is given to the experimental modeling of neuropathic pain in preclinical studies. Recently, an increased understanding of the neurophysiological plasticity of the nervous system in response to chronic pain has led to the discovery and development of novel pharmacological interventions that may have clinical utility in treating neuropathic pain.