This chapter examines when and why certain drugs became subject to global criminal prohibition in the twentieth century, beginning with the first international convention on the subject, led by the United States. Through these early negotiations, the United States succeeded in internationalizing its local prohibitionist movement, assuming not only geopolitical but also moral leadership on the world stage. The chapter shows that, under alarmist rhetoric allegedly grounded in the protection of public health and safety, the criteria used to define the illegality of certain substances were shaped more by the minorities who consumed them, the countries that produced them, and the political and economic interests at stake. The situation intensified in the 1970s with the “War on Drugs” policy, as international regulations adopted under the UN framework—especially the Vienna Convention, drafted in an environment marked by corruption, money laundering, and soaring criminal profits—consolidated the spread of authoritarian drug control policies across signatory states.