Because higher density of tobacco retailers is associated with greater tobacco use, U.S. communities seek ways to reduce the density and number of tobacco retailers. This approach can reduce the concentration of tobacco retailers in poorer communities, limit youth exposure to tobacco advertising, and prevent misleading associations between tobacco and health messaging. Communities can reduce the density and number of tobacco retailers by imposing minimum distance requirements between existing retailers, capping the number of retailers in a given geographic area, establishing a maximum number of retailers proportional to population size, and prohibiting sales at certain types of establishments, such as pharmacies, or within a certain distance of locations serving youth. Local governments use direct regulation, licensing, or zoning laws to enact these changes. We analyze each approach under U.S. constitutional law to assist communities in selecting and implementing one or more of these methods. There are few published legal opinions that address these strategies in the context of tobacco control. But potential constitutional challenges include violations of the Takings Clause of the Fifth Amendment, which protects property owners from onerous government regulations, and under the Fourteenth Amendment's Equal Protection and Due Process Clauses, which protect business owners from arbitrary or unreasonable regulations that do not further a legitimate government interest. Because there is an evidentiary basis linking the density of tobacco retailers to smoking rates in a community, courts are likely to reject constitutional challenges to carefully crafted laws that reduce the number of tobacco retailers. Our review of the relevant constitutional issues confirms that local governments have the authority to utilize laws and policies to reduce the density and number of tobacco retailers in their communities, given existing public health data. The analysis guides policy makers in crafting laws that comply with constitutional requirements by outlining the most important procedures and evidentiary justifications to use in development, implementation, and enforcement. This perspective also highlights the importance of reviewing state constitutions, statutes, and municipal codes and getting local input from attorneys and community stakeholders to assess the likely success of some methods over others.