The opioid epidemic stands alone as the defining public health crisis of our modern era, but America’s struggle with opioids and the opium plant from which it is derived dates back centuries. To comprehend the current crisis and how opioids became the leading cause of injury in the United States—surpassing even deaths from motor vehicle accidents—it is necessary to understand opioids through a historical lens. Much of what we struggle with today is not new, and many of our efforts to control opioids’ harms have historical precedents. This chapter traces opium’s journey to North America in the 1600s, through the development of morphine and heroin (initially marketed as “a safe family drug”) in the 1800s, to the introduction of OxyContin in 1996. Throughout these historical eras, a consistent pattern emerges: the pursuit of a nonaddictive opioid—what has been called the “holy grail of pain medicine”—has repeatedly ended in crisis.