Opioids are an important mode of treatment for many patients who suffer from acute and chronic pain. However, many opioids at therapeutic levels are associated with a spectrum of side effects that can limit quality of life and contribute to unintentional overdose death. Constipation, somnolence, urinary retention, pruritis, nausea, vomiting, confusion, dysphoria, euphoria, and other side effects are among the most common problems associated with mu opioid agonists. Recent research has focused on designing opioid-like molecules that have fewer side effects, including less risk for abuse and addiction. Delta and kappa opioid agonists are new chemical entities that are opioid-like and may have less respiratory depression than mu agonists but are equally effective as analgesics. These agonists have different properties than mu agonists and may provide an advantage in the treatment of pain. For example, it has been reported that delta opioid agonists have an antidepressant effect. This could be associated with both clinical benefits and untoward positive effects. Kappa opioids may have increased analgesia with much less abuse potential that traditional mu agonists. Several new delta and kappa agonist chemical entities are currently being investigated that may add to the clinician’s armamentarium in treating pain. This program discusses drugs in development that work primarily on delta and kappa receptors.