The United States is experiencing an epidemic of opioid overdose deaths. Many of the recent fatalities are associated with illicitly manufactured fentanyl, which is being added to heroin and counterfeit pain pills. The crisis is further exacerbated by the emergence of an increasing number of novel synthetic opioids (NSOs), including various fentanyl analogs and non-fentanyl compounds that display potent agonist actions at the μ-opioid receptor. Importantly, most users are unaware of their exposure to fentanyl and NSOs. Stemming the tide of opioid-related fatalities will require a coordinated multidisciplinary response from policy makers, law enforcement personnel, first responders, treatment providers, family members, and scientists. To this end, basic research in pharmacology can contribute significantly to mitigating the crisis through efforts to characterize the biological effects of NSOs, discover more effective antidotes for overdose rescue, and develop safer medications for treating addiction and alleviating pain.