Tobacco (Nicotiana sp.) is a powerful plant intoxicant and was widely used by contact period indigenous peoples throughout the North American west. Until recently, however, evidence of its prehistoric use has remained elusive. Recent advances in residue extraction and chemical identification techniques employing gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) are giving archaeologists the tools that are needed to address questions about the antiquity and nature of tobacco use. Recent chemical analyses of residues extracted from stone pipes and pipe fragments excavated at sites in the southern Pacific Northwest Coast of North America and Central California demonstrate tobacco was being smoked for at least 1100 years, a practice that continued into the historic period. Yet, it is likely that tobacco smoking began much earlier, and a number of anthropological questions about tobacco remain. In this chapter, we review recent research on the history of tobacco use in western North America, summarize ethnographic data, and discuss the theoretical framework of chemical studies and potential for future work. Our focus is on tobacco use by hunting-gathering-fishing societies who manipulated many different indigenous (“wild” and cultivated) tobaccos through selection to a degree that has been largely unappreciated. These cultural practices likely altered several tobacco species on a genetic and phenotypic level, perhaps even leading to the generation of unique varieties or species. We suggest several potential avenues of research, from historical questions of indigenous use and management to “Tobacco Sovereignty” and other modern-day applications for tribal communities.