Persistent chest wall pain is common after thoracotomy and is usually caused by recurrence or progression of malignancy. It should prompt efforts to identify and treat the causative disease. A minority of patients experience persistent pain not related to neoplasm. This pain may last for years, but is usually not severe. A small subset of these patients experience persistent severe pain, which may be debilitating. The pain may be owing to various causes. Diagnosis and treatment should be individualized and directed toward the causes believed to be present. First-line pharmacologic therapies include NSAIDs, tricyclic antidepressants, antiepileptics, and low-dose opioids. Some patients require more sophisticated treatment from multidisciplinary pain-management clinics. This treatment may include nerve blocks, physical therapy, sympathectomy, cryoneurolysis, or long-term neuromodulation with epidural analgesia or spinal cord stimulation. Because of the severe pain these patients may experience and the difficulty and expense associated with treatment, prevention may be the best strategy for dealing with this problem. Recent laboratory and clinical studies indicate that minimizing perioperative pain can suppress certain alterations in the nervous system that may prevent the genesis and maintenance of chronically painful conditions. This suggests that strategies for avoiding PTPS may begin with aggressive perioperative anesthetic and analgesic techniques. More effective application of knowledge already available from laboratory studies awaits further clinical trials. New drugs such as NMDA inhibitors hold promise for more effective treatment in the future.