The pistachio (Pistacia vera L.) is commercially cultivated in semi-arid regions around the globe. Archaeobotanical, genetic, and linguistic data suggest that the pistachio was brought under cultivation somewhere within its wild range, spanning southern Central Asia, northern Iran, and northern Afghanistan. Historically, pistachio cultivation has primarily relied on grafting, suggesting that, as with many Eurasian tree crops, domestication resulted from genetically locking hybrids or favored individuals in place. Plant domestication and dispersal research has largely focused on weedy, highly adaptable, self-compatible annuals; in this discussion, we present a case study that involves a dioecious long-lived perennial—a domestication process that would have required a completely different traditional ecological knowledge system than that utilized for grain cultivation. We argue that the pistachio was brought under cultivation in southern Central Asia, spreading westward by at least 2000 years ago (maybe a few centuries earlier to the mountains of modern Syria) and moved eastward only at the end of the first millennium AD. The seeds remain rare in archaeological sites outside its native range, even into the mid-second millennium AD, and may not have been widely cultivated until the past few hundred years.