The aim of this paper is to investigate the fundamental role of chemical kinetics on the performance maps of homogeneous charge compression ignition (HCCI) engines in terms of operability limits, engine efficiency, and emissions. The work focuses on a Ricardo E6 engine, highlighting the impact of different fuels (PRF80, PRF100, and ethanol) on ringing, misfire, and partial burn limits, as well as on several performance variables and pollutant emissions. The operability maps are calculated assuming proper criteria to identify the limits of the map in terms of ringing, misfire, and partial burn. Sensitivity analysis and rate of production analysis highlight the role of H2O2 in sustaining the combustion of ethanol at high exhaust gas recirculation (EGR) and air dilution with respect to PRF100 and PRF80 mixtures. The multizone model confirms that thermal stratification and crevices are the main factors responsible for the emissions of CO and unburned species. NOx are produced mainly via a thermal mechanism. Interaction of N2O with H and O radicals also plays a role, while a prompt mechanism does not significantly affect NOx emissions. Ethanol shows greater flexibility, lower pollutant emissions, and wider operability conditions with respect to engines fed with primary reference fuels. The paper highlights the potential of this multizone model in reproducing the engine performance. Nonreacting Computational Fluid Dynamics (CFD) simulations are first used to estimate heat and mass transfer coefficients. Then, the proposed model does not require further empirical or tuning parameters. Only the thresholds defining the operability maps are derived from the experiments and are the same for all the fuels and operating conditions investigated. The extensive comparison with a large set of experimental data shows the capability of the model to describe the effect of fuel composition and EGR the operability map, highlighting how such a tool can play an important role in understanding the chemistry controlling fuel reactivity and pollutant emissions in the different conditions. These information can support not only fuel and engine operation selection, but also their optimal design. As an example, the effects of boost and engine speed on the HCCI combustion are critically investigated, in terms of the extension of the operability region, engine thermal efficiency, and exhaust emissions.