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Compression ignition engines used in heavy-duty applications are typically powered by diesel fuel. The high energy density and feedstock abundance provide a continuing source for the immense energy demand. However, the heavy-duty transportation sector is challenged with lowering greenhouse gas and combustion by-product emissions, including carbon dioxide, nitrogen oxides, and particulate matter. The continuing development of engine management and combustion strategies has proven the ability to meet current regulations, particularly with higher fuel injection pressure. Nonetheless, a transition from diesel to a renewable alternative fuel source will play a significant role in reducing greenhouse gases while maintaining the convenience and energy density inherent in liquid fuels. Dimethyl ether is a versatile fuel that possesses combustion properties suitable for compression ignition engines and physical properties helpful for clean combustion.