Quantitative risk assessment (QRA) may inform regulatory decisions regarding tobacco products. Evaluation of human health risks from cigarette smoking requires an adequate assessment of the exposure, which is a challenging task in part because the concentration of chemicals in the respiratory tract is not constant. No regulatory guidance currently exists for exposure assessment of tobacco products, although examples exist in the peer-reviewed literature. The U.S. Environmental Protection Agency (EPA) provides guidance that addresses methods for quantitative evaluation of exposure and risk, which is useful and can be applied to tobacco products. Two different methods were developed to quantify inhalation exposure with machine-generated smoke yields from a market survey of U.S. cigarettes. The first method treats exposure to a chemical in smoke as a continuous process and estimates an exposure concentration by averaging the yields of the chemical from cigarettes consumed over the average daily volume of air inhaled by a user. The second method treats exposure to the chemical as discrete smoking sessions and estimates a respiratory concentration of the chemical via summation of discrete smoking sessions over the course of a day. Both methods incorporate standard exposure parameters to derive an upper-bound lifetime average exposure to the chemical. For simplicity and conservatism, both methods assume 100% retention of the chemical in the smoker’s body. The two methods provide risk estimates with relative percent differences within 30%; the first method was more conservative (i.e., risk-maximizing). Exposure assessment of tobacco products should be consistent with available evidence, guidance, and state of the science for risk assessment. These findings indicate that incremental modifications to exposure input assumptions do not materially affect the QRA results.