Major depressive disorder is a medical condition that includes abnormalities of affect and mood, cognition, and physical functioning. In particular, as many as 76% of patients suffering from depression are found to report somatic symptoms, including various types of pain such as headaches, stomach pain, back pain, and vague, poorly localized pain. Although the pathophysiology of depression is still unknown, there is significant evidence for abnormalities of the norepinephrine (NE) and serotonin (5-HT) neurotransmitter systems in depressive disorders. Interestingly, both 5-HT and NE also appear to exert analgesic effects via descending pain pathways and therefore play a modulating role in pain. There are many effective antidepressant treatments available. However, residual symptoms are relatively common, among both partial responders and responders without remission. A recent study from our group has shown that responders who have not achieved remission have significantly more somatic symptoms than remitters following 8 weeks of treatment with fluoxetine. These data may suggest that antidepressants that are particularly effective in the treatment of pain and painful physical symptoms may yield higher remission rates in major depressive disorder.