Delta (δ) opioid receptors (DORs) are part of circuits involved in many physiological functions including the modulation of pain. Activation of DORs appears to mediate antinociception and antihyperalgesia in many conditions including stress, chronic pain, opioid-induced hyperalgesia (OIH), and opiate tolerance. δ Opioid signaling also extensively interacts with the mu (μ) opioid system, resulting in modulation of pain transmission. Multiple mechanisms may underlie DOR modulation of pain including the synergistic interaction between μ and δ opioid receptors and between spinal and supraspinal sites of action, enhanced endogenous enkephalinergic tone, potential μ-δ oligomers and modulation of plasma membrane receptor trafficking.