The culmination of the widespread overprescription of opioids, a resurgence of heroin use, and increased accessibility and use of illicit synthetic opioids is commonly referred to as the opioid epidemic in North America. This article is not intended to provide a comprehensive systematic literature review, but rather summarized recent publications and online governmental reports and datasets for English-written literature primarily published between January 1, 2015 and July 1, 2020. In both the United States and Canada, opioids represent one of the most widely prescribed classes of medications. According to the US Centers for Disease Control and Prevention (CDC), an unprecedented increase in the use of opioid pain relievers has led to one of the worst drug overdose epidemics in US history and continues to be an ongoing major public health crisis based on recent Centers for Disease Control and Prevention mortality data, where almost two-thirds of all overdose deaths still involve opioids, including heroin and illicit opioids. In addition to the high mortality rates in both the United States and Canada, there has also been an increase in emergency department visits for nonmedical use of opioid pain relievers, along with additional individuals seeking treatment for opioid addiction, and a rise in neonatal abstinence syndrome. This article highlights the history, underlying issues, ongoing national regulatory efforts, and future strategies and therapies to help mitigate the opioid crisis in North America.