Naloxone is a specific, high affinity opioid antagonist that has been used to treat suspected or confirmed overdose for more than 40 years. Naloxone use was initially confined to an emergency room setting, but the dramatic rise in opioid overdose events over the past two decades has, with increasing frequency, shifted naloxone use to first responders including police, emergency medical technicians, and the friends and family of overdose victims. The opioids responsible for overdose events have also evolved, from prescription opioids to heroin and most recently, very high potency synthetic opioids such as fentanyl. In 2016, synthetic opioids were linked to more overdose fatalities than either prescription opioids or heroin. In this review, I will discuss the evolution and use of naloxone products by first responders and the development of additional rescue medications in response to the unprecedented dangers posed by synthetic opioids.