Homogeneous charge compression ignition (HCCI) combustion in diesel engines can provide cleaner operation with ultralow NOx and soot emissions. While HCCI combustion has generated significant attention in the last decade, however, till date, it has seen very limited application in production diesel engines. HCCI combustion is typically characterized by earlier than top-dead-center (pre-TDC) phasing, very high-pressure rise rates, short combustion durations, and minimal control over the timing of the combustion event. To offset the high reactivity of the diesel fuel, large amounts of exhaust gas recirculation (EGR) (30–60%) are usually applied to postpone the initiation of combustion, shift the combustion toward TDC, and alleviate to some extent, the high-pressure rise rates and the reduced energy efficiency. In this work, a detailed analysis of HCCI combustion has been carried out on a high-compression ratio (CR), single-cylinder diesel engine. The effects of intake boost, EGR quantity/temperature, engine speed, injection scheduling, and injection pressure on the operability limits have been empirically determined and correlated with the combustion stability, emissions, and performance metrics. The empirical investigation is extended to assess the suitability of common alternate fuels (n-butanol, gasoline, and ethanol) for HCCI combustion. On the basis of the analysis, the significant challenges affecting the real-world application of HCCI are identified, their effects on the engine performance quantified, and possible solutions to overcome these challenges explored through both theoretical and empirical investigations. This paper intends to provide a comprehensive summary of the implementation issues affecting HCCI combustion in diesel engines.