While vehicles are becoming more efficient, the properties of conventional fuels continue to limit the performance of internal combustion engines in most cars and trucks currently on U.S. roads. The Department of Energy (DOE) Co-Optimization of Fuels & Engines (Co-Optima) initiative is bringing together top scientists, engineers, and analysts from nine national laboratories with more than 20 university and industry partners across the country to investigate fuels and engines as dynamic design variables that can work together to boost efficiency and performance, while minimizing emissions. Applications include the entire on-road fleet, from light-duty (LD) passenger cars to heavy-duty (HD) freight trucks. The objective scientific outcomes of this initiative will provide American industry and policymakers with the knowledge, data, and tools needed to decide which changes could prove most viable and beneficial for drivers, businesses, and the environment. Potential benefits include dramatic improvements in vehicle fuel economy and increases in the use of domestically sourced fuel for transportation, in turn creating new U.S. jobs and keeping energy dollars in the United States, while reducing emissions and costs for consumers and commercial operators at the pump.