Depression is a common accompaniment of pain, particularly when pain is unremitting. The use of a variety of antidepressant medications is associated with pain reduction, an effect that is independent of the mood-enhancing qualities of these drugs. This pain relief is a consequence of a wide variety of actions of antidepressants on the neuroregulatory mechanisms associated with pain perception and transmission. The older tricyclic antidepressants (TCAs) and the newer 'balanced' reuptake inhibitors (such as duloxetine) seem to be more efficacious in terms of providing pain relief than the selective serotonin reuptake inhibitors (SSRIs). Unfortunately, adverse effects are not uncommon during antidepressant use, particularly with TCAs. It is now becoming apparent that TCAs can have an analgesic effect when applied topically and that this effect is produced by peripheral mechanisms rather than systemic uptake. Antidepressants remain a major therapeutic tool in the management of chronic pain.