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Over the next decades to come, fossil fuel powered Internal Combustion Engines (ICE) will still constitute the major powertrains for land transport. Therefore, their impact on the global and local pollution and on the use of natural resources should be minimized. To this end, an extensive fundamental and practical study was performed to evaluate the potential benefits of simultaneously co-optimizing the system fuel-and-engine using diesel as an example. It will be clearly shown that the still unused co-optimizing of the system fuel-and-engine (including advanced exhaust after-treatment) as a single entity is a must for enabling cleaner future road transport by cleaner fuels since there are large, still unexploited potentials for improvements in road fuels which will provide major reductions in pollutant emissions both in vehicles already in the field and even more so in future dedicated vehicles.