The peyote cactus, Lophophora williamsii, is presently classified as a Schedule 1 Controlled Substance in the USA, with an exemption for use as a sacrament in bona fide religious ceremonies of the Native American Church (NAC). Any botanist or other researcher seeking to work with peyote or any of its alkaloids, must comply with applicable (nontrivial) regulatory requirements. This paper presents an examination of the prohibition efforts that paved the way for current peyote regulation, accompanied by documentation of the religion-based political origins of such efforts, which involved the “acculturation” of Native Americans (i.e., the destruction of American Indian cultures). We also look at the historical emergence of a nationally organized and coordinated effort by missionaries and other prohibitionists to sell a federal anti-peyote law to Congress, which manifested itself repeatedly over a period of more than fifty years, before finally realizing success in the Controlled Substances Act of 1970. In view of ongoing changes in the legal/regulatory status of Cannabis sp. (another Schedule 1 plant that was targeted for illegality during the prohibitionists’ rise to political predominance), we compare and contrast the two plants with speculation on peyote’s future. key words: Lophophora williamsii, peyote, religion, drug prohibition, American Indian culture, cannabis