In December 2014 the United States Department of Justice released a policy statement directing United States Attorney’s Offices to consult with Native Nations regarding growing and selling marijuana on sovereign Native nation lands. Additionally, rather than pursue blanket enforcement, the statement presented eight enforcement priorities. By August 2019 thirty-three states had legalized medical marijuana; eleven of these plus the District of Columbia had also legalized recreational marijuana. Given the positive impacts seen in these states (increased tax revenue and reductions in substance abuse and crime rates), some Native Nations passed their own laws legalizing medical, recreational, or agricultural cannabis. However, these efforts have been obstructed by the US Drug Enforcement Agency’s contradictory and erratic actions. This article examines the impacts of this targeted differential enforcement of cannabis laws on Native Nations’ cannabis decisions by discussing the racialized development of cannabis laws, how legalization differs between states and Native Nations, impacts of legalization on Native Nations’ sovereignty practices, concerns of Native nation citizens about legalization (including opposition to legalization), and legalization’s potential long-term effects. Finally, the impacts of these national actions are shown in a brief examination of the Eastern Band of Cherokee Indians’ recent movement toward legalization of medical marijuana.