Sustainably produced biofuels are being discussed intensively as one possible component in the energy scenarios for future ground transportation, especially when they are derived from lignocellulosic biomass. Traditionally, research activities on their production focus on the synthesis process, while leaving their combustion properties to subsequent evaluation by a different community. The present article adopts an integrative view of engine combustion and fuel synthesis, focusing on the chemical aspects as the common denominator. We wish to demonstrate that fundamental understanding of the combustion process can be instrumental to derive design criteria for the molecular structure of fuel candidates that can then be targets for the analysis of synthetic pathways and the development of catalytic production routes. With such an integrative approach to fuel design, it will be possible to improve systematically the entire system, spanning biomass feedstock, conversion process, fuel, engine, and pollutants with a perspective to improve the carbon footprint, increase efficiency, and reduce emissions of the transportation sector along the whole value chain.