Tobacco and the various plants of the genus Nicotiana that produce it have a complex history in lowland South America. This brief examination of tobacco’s history illuminates the importance for understanding how the diversity of species of Nicotiana shaped its early use, including the tendency toward the selection of plants with high nicotine content. It is very likely that hunter-gathers of the eastern Andes first utilized tobacco, spreading several species to the north of the continent while early horticulturalists expanded tobacco’s distribution toward Amazonia and the humid lowlands. The high variation in the patterning and spatial distribution of techniques in tobacco use seem to correlate with distribution of Nicotiana species in the eastern Andes and into the lowlands. However, a lack of archaeological data on tobacco in South America continues to raise questions. Nonetheless, advances made in North American archaeology reveal broad usage of Nicotiana species, including several beyond those best known for their selection by humans, primarily N. rustica and N. tabacum. The colonial period led to the commodification of tobacco, and Amazonia played a role in its production for the global economy from early on. Despite this, tobacco continued to hold strong ties to Amazonia’s indigenous past as it was cultivated in enriched anthropogenic soils characteristic of Amerindian settlement sites, which are still used – for indigenous and non-indigenous populations alike – for tobacco production today. In this manner, tobacco cultivation in Amazonia still reflects some of its deep history derived from indigenous peoples of the region, remaining both a sacred plant and a staple crop.