Differential diagnosis is the systematic consideration of the possible cause of signs and symptoms. It requires establishing an anatomic diagnosis, in which the site of pathology is identified, and then an etiiologic diagnosis of the causal pathologic agent. The differential diagnosis is based on a knowledge of the pathophysiology of 1) the presenting signs and symptoms, and 2) the natural history of various diseases and their causative agents. Consequently, the accuracy and reliability of the differential diagnosis is limited by a lack of knowledge about the pathophysiology of various diseases that produce chronic pain. Most painful conditions affecting ectodermally derived tissues are relatively easily localized; the major problems are in the diagnosis of central nervous system pain syndromes and in our knowledge about the pathophysiology of painful neurologic disorders. The anatomic diagnosis of painful diseases of mesodermal and endodermal tissues may be difficult because of the phenomena of referred pain and tenderness. The etiologic diagnosis is made difficult by our lack of knowledge about how various pathologic processes activate nociceptors in these tissues. Finally, the differential diagnosis of chronic pain requires information about the psychological characteristics of the patient and how emotional and higher cognitive functions influence the perception of pain.