For sustainable future mobility and power generation applications, there is a compelling need to develop flex-fuel engines that operate with multiple regional or season-specific biofuels. Also, it has become imperative to resolve conventional diesel engines’ pollutant emission and performance problems. The present research investigated the advanced diesel combustion mode of Homogeneous Charge Compression Ignition (HCCI) by modifying a production light-duty diesel engine. Seven different gasoline-like high volatility and low reactivity alternative fuels, methanol, ethanol, isopropanol, isobutanol, ethyl acetate, acetone, and diisopropyl ether, were used to operate the HCCI engine. Significantly low oxides of nitrogen and near-zero smoke emissions were produced by the HCCI engine. The 3-D computational fluid dynamics simulations of HCCI combustion in the test engine were conducted to elucidate the experimental findings. The simulations helped to identify the in-cylinder sources of unburned hydrocarbon and carbon monoxide emissions. The strategies for reducing these emissions were investigated by selecting the most suitable ignition improvers, piston bowl shape, and compression ratio. Further, a dynamic fuel blending system was developed and implemented to achieve varying fuel blend requirements according to the load demand to extend the HCCI engine operating load range. In this seminar talk, I will discuss the scientific reasons behind the improved performance and reduced emission metrics of HCCI engine operation with renewable biofuel blends.