Opioid overdose deaths in the United States increased sharply over the last decade leading the President to declare a national emergency. The neurobiology of opioid addiction is explored in conjunction with the historical events preceding the current epidemic. A patient-centric perspective is provided along with rationale for contemporary Medical Assisted Therapy (MAT) options to safely reduce overdose deaths and other preventable consequences of prescription misuse and heroin abuse. A multidisciplinary medical provider approach is essential, in addition to legislative efforts to reduce current regulatory burdens that reduce access to MAT in many settings. This review introduces a new Missouri Medicine series intended to explore key concepts to simultaneously reduce opioid prescribing, while effectively managing acute and chronic pain across complex healthcare settings.