Opioids are widely used in the treatment of severe pain. The clinical use of the opioids is limited by serious side effects such as respiratory depression, constipation, development of tolerance, and physical dependence and addiction liabilities. Most of the currently available opioid analgesics exert their analgesic and adverse effects primarily through the opioid mu receptors. A large number of biochemical and pharmacological studies and studies using genetically modified animals have provided convincing evidence regarding the existence of modulatory interactions between opioid mu and delta receptors. Several studies indicate that delta receptor agonists as well as delta receptor antagonists can provide beneficial modulation to the pharmacological effects of mu agonists. For example, delta agonists can enhance the analgesic potency and efficacy of mu agonists, and delta antagonists can prevent or diminish the development of tolerance and physical dependence by mu agonists. On the basis of these observations, the development of new opioid ligands possessing mixed mu agonist/delta agonist profile and mixed mu agonist/delta antagonist profile has emerged as a promising new approach to analgesic drug development. A brief overview of mu-delta interactions and recent developments in identification of ligands possessing mixed mu agonist/delta agonist and mu agonist/delta antagonist activities is provided in this report.