Much of the progress in reducing cigarette smoking and tobacco-related morbidity and mortality among youth and adults is attributable to population-level strategies previously described in the context of the Tobacco Control Vaccine. The retail environment is used heavily by the tobacco industry to promote and advertise its products, and variations in exposure to and characteristics of the retail environment exist across demographic groups. It is therefore also an essential environment for further reducing smoking, as well as ameliorating racial, ethnic and socioeconomic tobacco-related disparities. This commentary provides an overview of the importance of incorporating strategies focused on the tobacco retailer environment (availability; pricing and promotion; advertising and display; age of sale; and retail licensure) as part of a comprehensive approach to tobacco prevention and control. To reach tobacco endgame targets, such innovative strategies are a complement to, but not a replacement for, long-standing evidence-based components of the Tobacco Control Vaccine.