Antidepressants exhibit a number of pharmacological mechanisms, including norepinephrine and serotonin modulation, direct and indirect effects on opioid receptors, inhibition of histamine, cholinergic and N-methyl-D-aspartate receptors, and inhibition of ion channel activity. Although it is not entirely clear which mechanisms produce analgesia and to what extent, the available animal and clinical trials data indicates that tricyclic antidepressants are effective in treating many types of pain. The newer selective serotonin reuptake inhibitors also appear to be effective for chronic headache and other non-neuropathic forms of chronic pain but are not as well studied. This article reviews the current basic and clinical research on antidepressants in pain management.