In recent years the prescription opioid overdose epidemic has decreased, but has been more than offset by increases in overdose caused by fentanyl and fentanyl analogues. Opioid overdose patients should receive naloxone if they have significant respiratory depression and/or loss of protective airway reflexes. Patients who receive naloxone should be observed for recurrent opioid effects. Patients with opioid overdose may be admitted to the intensive care unit for naloxone infusions, treatment of noncardiogenic pulmonary edema, autonomic instability, or sequelae of hypoxia-ischemia or cardiac arrest. Primary and secondary prevention are important to reduce the number of people with life-threatening opioid overdose.