A range of chemicals from very volatile to semivolatile organic compounds are emitted from spray polyurethane foam (SPF) insulation. SPF installation procedures and environments can vary widely, and the emissions, transport, and fate of these chemicals in the indoor environment after SPF installation are not well characterized. To begin to understand exposure to emissions from SPF and to identify and characterize the uncertainty in assessing chemical exposures, a proof-of-concept multizone indoor model was developed to estimate indoor air concentrations of chemicals emitted from SPF over time. The model supported the development of different approaches for characterizing the emissions of volatile and semivolatile organic compounds and for predicting short- and long-term emissions and subsequent air concentrations. It also incorporated estimates for a wide range of parameters that influence emission and subsequent exposure from SPF. A sensitivity analysis was performed to explore the impact of model inputs, including those considered the most influential and those for which there is uncertainty because of a lack of data. Model inputs included the location and type of SPF foam; the chemical-specific diffusion and partitioning coefficients; the temperature and ventilation rates of zones within the residence; and the impact of engineering controls, such as increased ventilation during installation. Sensitivity analysis results identified trends and relations between model inputs and outputs. Additional experimental data are needed to calibrate the model and to reduce uncertainty of model estimates. In particular, information is needed to characterize emissions within the first 24 h after spray application, to characterize longer-term mass transfer of chemicals from SPF, and to describe interzonal air flow and leakage rates between attics, living spaces, and crawl spaces.