From the 1840s through the end of the nineteenth century, the southern Appalachian region emerged as the United States’ most important supplier of so-called crude botanical drugs to the growing pharmaceutical industry centered in the northeastern and Midwestern United States. This article investigates the role of ecology, markets, and local culture in sustaining this trend. It argues that mountain entrepreneurs and the remarkable biodiversity of the Appalachian ecosystems combined with harvesters’ intimate knowledge of the landscape and a local commitment to common rights to make the region the nation’s foremost supplier of crude drugs. The botanical drug trade provides an interesting divergence from the typical narrative of commodification. Instead of restructuring nature into productive landscapes governed by capitalist values, the commodification of medicinal herbs helped reinforce common rights and expand ecological knowledge of the landscape. This process shaped late nineteenth-century Appalachian life by increasing the importance of the forests in rural economies. Although mountain people continued to harvest medicinal herbs well into the twentieth century, resource depletion, habitat destruction, economic changes, and other factors fundamentally changed the dynamics of this gathering commons.