Research concerning psychiatric issues relating to opioid drugs currently focuses primarily on their role in reinforcing addictive behaviors, given the recent proliferation of lethal abuse of illicit opiates in the United States and around the world. In contrast, this article will review the mechanism of action of opioids in affective disorders and the available evidence and potential for their use, especially in the treatment of resistant major depression. Buprenorphine is the opioid derivative of special interest; we review this and other opioid derivatives, highlighting the growing role of opioids in treating depressive illnesses and other related psychopathologies.