Chronic pain represents one of the most important public health problems and, in addition to classical analgesics, antidepressants are an essential part of the therapeutic strategy. This article reviews available evidence on the efficacy and safety of antidepressants in major chronic pain conditions; namely, neuropathic pain, headaches, low back pain, fibromyalgia, irritable bowel syndrome (IBS) and cancer pain. Studies, reviews and meta-analyses published from 1991 to March 2008 were retrieved through MEDLINE, PsycINFO and the Cochrane database using numerous key words for pain and antidepressants. In summary, evidence supports the use of tricyclic antidepressants in neuropathic pain, headaches, low back pain, fibromyalgia and IBS. The efficacy of the newer serotonin and norepinephrine reuptake inhibitors is less supported by evidence, but can be recommended in neuropathic pain, migraines and fibromyalgia. To date, evidence does not support an analgesic effect of serotonin reuptake inhibitors, but beneficial effects on well-being were reported in several chronic pain conditions. These results are discussed in the light of current insights in the neurobiology of pain, the reciprocal relationship between pain and depression, and future developments in this field of research.