Neuropathic pain syndromes arise from dysfunction of the nerve itself, through traumatic or nontraumatic injury. Unlike acute pain syndromes, the pain is long-lasting and does not respond to common analgesic therapies. Drugs that disrupt nerve conduction and transmission or central sensitization, currently the only effective treatments, are only modestly effective for a portion of the patients suffering from neuropathic pain and come with the cost of serious adverse effects. Neurodegeneration, as a reaction to nerve trauma or chronic metabolic or chemical intoxication, appears to be an underlying cause of neuropathic pain. Identifying mechanisms of neurodegeneration and designing neuroprotective therapies is an ambitious goal toward treating or even preventing the development of these disabling disorders.