To drastically reduce the emission of greenhouse gases, the development of future internal combustion engines will be strictly linked to the development of CO2 neutral fuels (e.g. biofuels and e-fuels). This evolution implies an increase in development complexity, which needs the support of engine 3D-CFD simulations. Francesco Cupo presents approaches to accurately describe fuel characteristics and knock occurrence in SI engines, thus improving the current simulation capability in investigating alternative fuels and innovative combustion processes. The developed models are successfully used to investigate the influence of ethanol-based fuels and water injection strategies on knock occurrence and to conduct a virtual fuel design for and engine operating with the innovative SACI combustion strategy.