The opioid epidemic is at the epicenter of the drug crisis, resulting in an inconceivable number of overdose deaths and exorbitant associated medical costs that have crippled many communities across the socioeconomic spectrum in the United States. Classic medications for the treatment of opioid use disorder predominantly target the opioid system and thus have been underutilized, in part due to their own potential for abuse and heavy regulatory burden for patients and clinicians. Opioid antagonists are now evolving in their use, not only to prevent acute overdoses but as extended-use treatment options. Strategies that target specific genetic and epigenetic factors, along with novel nonopioid medications, hold promise as future therapeutic interventions for opioid abuse. Success in increasing the treatment options in the clinical toolbox will, hopefully, help to end the historical pattern of recurring opioid epidemics.