Traditional tobacco product (cigarettes and smokeless tobacco) and polytobacco use rates are significantly higher among rural adolescents and adults compared to their nonrural counterparts. Such disparities are due to several factors that promote tobacco use initiation and continuation, including individual-level psychopharmacological factors and structural-level factors such as fewer tobacco control efforts (e.g., fewer smoke-free policies and lower tobacco excise taxes), targeted tobacco marketing, less access to health-relevant resources, and more positive cultural norms surrounding tobacco use in rural communities. In this review, we use cumulative disadvantage theory as a framework for understanding how psychopharmacological and structural-level factors serve as drivers of tobacco use in rural areas. We start by describing how structural-level differences between rural–nonrural communities impact psychopharmacological influences and, when available, how these factors influence tobacco use. We conclude by discussing the interplay between factors, providing suggestions for ways to assess our application of cumulative disadvantage theory empirically and making recommendations for research and policy implementation in rural areas. (PsycInfo Database Record (c) 2021 APA, all rights reserved)