The United States is in the midst of a prolonged and growing epidemic of accidental and preventable deaths associated with overdoses of licit and illicit opioids. For more than 3 decades, naloxone has been used by emergency medical personnel to pharmacologically reverse overdoses. The peers or family members of overdose victims, however, are most often the actual first responders and are best positioned to intervene within an hour of the onset of overdose symptoms. Data from recent pilot programs demonstrate that lay persons are consistently successful in safely administering naloxone and reversing opioid overdose. Current evidence supports the extensive scaleup of access to naloxone. We present advantages and limitations associated with a range of possible policy and program responses.