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The National Highway Traffic Safety Administration (NHTSA) has been leading U.S. efforts related to the rulemaking process for Corporate Average Fuel Economy (CAFE) standards. Argonne National Laboratory, a U.S. Department of Energy (DOE) national laboratory, has developed a full-vehicle simulation tool called Autonomie that has become one of the industry standard tools for analyzing vehicle performance, energy consumption, and technology effectiveness. Through an Interagency Agreement, the DOE Argonne Site Office and Argonne National Laboratory have been tasked with conducting full vehicle simulation to support NHTSA CAFE rulemaking. This paper presents an innovative approach focused on large-scale simulation processes spanning standard regulatory driving cycles, diverse vehicle classes, and various timeframes. A key element of this approach is Autonomie’s capacity to integrate advanced engine technologies tailored to specific vehicle classes and powertrains.