Overdose due to opioid abuse is an ever increasing problem, especially in the United States, with the last few years seeing a dramatic rise in the number of synthetic opioid-related deaths. The pure opioid antagonist naloxone has been used in a clinical setting as an antidote to opioid overdose for decades. Recent data suggest that the number of patients requiring multiple doses of naloxone is growing likely caused by the increased number of intoxications with potent synthetic opioids such as fentanyl and its derivatives. Treating clinicians in both emergency departments and pre-hospital settings should be aware that they may need to escalate to higher doses of naloxone, with repeat doses or IV infusions required, when treating patients who have overdosed on synthetic opioids. Moving forward, a combination of improved access to naloxone in a pre-hospital setting, an increase in community-based training, including the likely requirement of rapid or higher dose naloxone administration for treatment of synthetic opioid overdose, and a better understanding of the toxicology of high potency synthetic opioids, are required to decrease the number of fatalities stemming from the current opioid crisis.