The United States is in the midst of an opioid epidemic, with current estimates placing the number of opioid-related deaths at more than 70,000 per year. This symposium will provide an update on the current state of the epidemic, with an eye towards challenges that we will face in the coming years. This symposium will also describe novel pharmacokinetic and pharmacodynamic approaches to combat opioid addiction and overdose, such as opioid-specific vaccines and pseudo-irreversible opioid receptor antagonists. Finally, this symposium will discuss innovative approaches to reduce opioid addiction through the development of non-opioid (or opioid-sparing) strategies to relieve pain.