Since 1999, annual opioid-related overdose (ORO) mortality has increased more than six-fold. In response to this crisis, the US Department of Health and Human Services outlined a 5-point strategy to reduce ORO mortality which included the widespread distribution of naloxone, an opioid antagonist that can rapidly reverse an opioid overdose. Increased distribution has been facilitated by the implementation of naloxone access laws in each US state aimed at increasing community access to naloxone. While these laws differ from state-to-state, most contain mechanisms to enable pharmacists to dispense naloxone without a patient-specific prescription. These laws have enhanced community naloxone distribution, both from pharmacies and overdose education and naloxone distribution programs, and produced positive effects on ORO mortality. However, a growing body of evidence has revealed that significant barriers to naloxone access from pharmacies remain, and annual ORO deaths have continued to climb. Given these concerns, there has been a push among some clinicians and policymakers for the US Food and Drug Administration to re-classify naloxone as an over-the-counter (OTC) medication as a means to further increase its accessibility. If an OTC transition occurs, educational outreach and funding for clinical innovations will continue to be crucial given the important role of health professionals in recommending naloxone to people at risk for experiencing or witnessing an ORO. Recognizing the severity of the ORO public health crisis, we believe transitioning formulations of naloxone approved for layperson use to OTC status would result in a net benefit through increased access. However, such a change should be combined with measures to ensure affordability.