Depression is a common mental disorder that affects people of all ages across the world. All current pharmacological interventions are based on the monoamine theory of depression and aim to increase the concentrations of monoamines in the brain. However, since many patients show no response or do not tolerate conventional therapies, there is an urgent need to identify new therapeutic targets, explore new molecular pathways and develop novel drugs against depression. Opioids, a class of compounds used against chronic pain, have major analgesic properties, but they are also well known for their anxiolytic and antidepressant effects. In preclinical and clinical studies, some opioids showed encouraging results to alleviate depression-like symptoms. Although our knowledge about the antidepressant effects of opioids stretches back to the late „70s, we still have a long way to cover. Predominantly, a clear understanding about their mode of action as well as the opioid-associated issues of addiction and convulsions, are the main challenges that need to be addressed before we will see opioid compound used in the clinic against depression.