Traditional CI engines focus on close to isochoric heat release, which presumably gives high theoretical efficiency. However, an isochoric heat release also elevates the in-cylinder temperature—giving higher NOx emissions and heat losses, while keeping the maximum pressure high. Advancing the CI engine technology requires disruption of in-cylinder conditions and heat release shapes. Such disruptions are enabled by tailoring the injection strategies and/or the auto-ignition features of fuels. This chapter describes pathways—each with unique features—to unlock the potential of the CI engine. The first approach adopts multiple injection strategy aimed to produce heat at a constant pressure, commonly known as isobaric combustion. Isobaric combustion has a great prospect in reducing heat transfer losses, while sustaining high exhaust enthalpy for extraction in a waste heat recovery system. The only apparent vulnerability of isobaric combustion is the high soot emission, which is catalyzed—according to optical diagnostic techniques—by injection of spray jets into oxygen-deprived regions. Employing multiple injectors and an additional expansion stage has the prospect to eliminate soot emission. The second approach involves operating at extreme conditions where fuel chemistry becomes irrelevant. All fuels—regardless of the octane number—exhibit diffusion-driven features. The engine, in fact, becomes fuel flexible, having the potential to use sustainable fuels—without being restrained by the auto-ignition properties of the fuels. While fuel auto-ignition in the first two approaches is driven by diffusion, the third approach considers employing advanced combustion regimes with enhanced premixing features—namely homogenous charge compression ignition (HCCI) and partially premixed combustion (PPC). Achieving stable HCCI and PPC operation requires co-optimizing of the in-cylinder temperature/pressure trajectory with the octane number of fuel.