The genus Cannabis has a complex history, with great variations in the genus itself, as well as in its current uses worldwide. Today, it is the most commonly used psychoactive substance, with 209 million users in 2020. The legalization of cannabis for medicinal or adult use is complex. From its origins as a therapeutic agent in 2800 bc China, to the current knowledge on cannabinoids and the cannabinoid system, to the complex status of cannabis regulation across continents-knowledge gained from the history of cannabis use can inform research on cannabis-based treatments for patients with medical conditions that remain challenging in 21st century medicine, warranting research and evidence-based policy options. Changes in cannabis-related policymaking, scientific advances, and perceptions may result in increasing patient inquiries about its medicinal usage, regardless of personal opinions, thus meriting education and training of clinicians. This commentary outlines the long history of cannabis use, its current therapeutic potential from a regulatory research perspective, and the continued challenges in research and regulation in the ever-changing era of modern cannabis use. It is crucial to understand the history and complexity of cannabis use as medicine to better understand its potential for clinical therapeutics and the effects of modern-day legalization on other health- and society-related issues.