Tricyclic antidepressants, together with anticonvulsants, are considered to be first-line drugs for the treatment of neuropathic pain. Antidepressants are analgesic in patients with chronic pain and no concomitant depression, indicating that the analgesic and antidepressant effects occur independently. The analgesia induced by these drugs seems to be centrally mediated but consistent evidence also indicates a peripheral site of action. Several pharmacological mechanisms account for their antinociceptive effect but the inhibition of monoamine transporters (and, consequently, the facilitation of descending inhibition pain systems) is implicated on the basis of mechanistic and knockout-mouse studies. However, pain is a common symptom of depression, and depression is frequent in chronic pain patients, supporting the hypothesis that pain and depression share some common biochemical mechanisms. We suggest that antidepressants have a genuine analgesic effect and that research into their mechanisms of action will help to facilitate the development of new drugs.