The economic burden of depression is substantial. The condition is highly prevalent, with both psychiatric and physical symptoms that often inflict pain. The chronic and often debilitating nature of depression results in costly medical therapies, as well as impaired workplace productivity. As a result, the overall economic burden of depression is comparable to that of serious physical illnesses, such as cancer and heart disease. This article presents an overview of the economic burden of depression and provides background on the relationship between depression and pain in this context. Research findings are also presented on the economic burden associated with a particular manifestation of pain among depressed patients, fibromyalgia. When painful physical symptoms accompany the already debilitating psychiatric and behavioral symptoms of depression, the economic burden that ensues for patients and their employers increases considerably. On purely economic grounds, more aggressive outreach may be warranted for patients with depression and comorbid pain to initiate treatment before symptoms are allowed to persist. However, more research is needed to assess the comprehensive economic impact that depression with painful physical symptoms can have on society.