Aftertreatment system design involves multiple tradeoffs between engine performance, fuel economy, regulatory emission levels, packaging, and cost. Selection of the best design solution (or “architecture”) is often based on an assumption that inherent catalyst activity is unaffected by location within the system. However, this study acknowledges that catalyst activity can be significantly impacted by location in the system as a result of varying thermal exposure, and this in turn can impact the selection of an optimum system architecture. Vehicle experiments with catalysts aged over a range of mild to moderate to severe thermal conditions that accurately reflect select locations on a vehicle were conducted on a chassis dynamometer. The vehicle test data indicated CO and NOx could be minimized with a catalyst placed in an intermediate location. The vehicle data was also used to calibrate a single channel monolith catalyst model (via adjustment of kinetic parameters) to match each of the different aged conditions. The calibrated model forecasted an optimum configuration with a close-coupled front brick and an underbody rear brick. Subsequent vehicle experiments confirmed the model predictions. The modeling approach can be extended to investigate an optimum architecture for other applications as well.