Antidepressant drugs have been used successfully in the treatment of chronic pain syndromes. Clinical trials have supported the use of these drugs for pain and the depression that often accompanies pain syndromes. Although the exact mechanisms of action have not been clearly elucidated, it has been suggested that these agents have analgesic properties independent of their antidepressant effect on mood and behavior. Pain patients without concomitant depression experienced pain relief with antidepressant therapy; these patients represent the most convincing evidence that antidepressant drugs have a direct analgesic effect. Studies presented in this paper support the clinical efficacy of antidepressant medications in the treatment of patients suffering from headaches (migraine, tension, and mixed types), diabetic neuropathy, arthritis, and facial pain. These data also suggest that antidepressant drugs may be effective in the treatment of postherpetic neuralgia, back pain, and pain from mixed etiologies; however, data for these pain syndromes are less clear, and, thus, further testing is required.