Opioid receptors are widely expressed in the brain, and the opioid system has a key role in modulating mood, reward processing and stress responsivity. There is mounting evidence that the endogenous opioid system may be dysregulated in depression and that drug treatments targeting mu, delta and kappa opioid receptors may show antidepressant potential. The mechanisms underlying the therapeutic effects of opioid system engagement are complex and likely multi-factorial. This chapter explores various pathways through which the modulation of the opioid system may influence depression. These include impacts on monoaminergic systems, the regulation of stress and the hypothalamic-pituitary-adrenal axis, the immune system and inflammation, brain-derived neurotrophic factors, neurogenesis and neuroplasticity, social pain and social reward, as well as expectancy and placebo effects. A greater understanding of the diverse mechanisms through which opioid system modulation may improve depressive symptoms could ultimately aid in the development of safe and effective alternative treatments for individuals with difficult-to-treat depression.