Engine experiments and multi-dimensional modeling were used to explore Reactivity Controlled Compression Ignition (RCCI) to realize highly-efficient combustion with near zero levels of NOx and PM. In-cylinder fuel blending using port-fuel-injection of a low reactivity fuel and optimized direct-injection of higher reactivity fuels was used to control combustion phasing and duration. In addition to injection and operating parameters, the study explored the effect of fuel properties by considering both gasoline-diesel dual-fuel operation, ethanol (E85)-diesel dual fuel operation, and a single fuel gasoline-gasoline+DTBP (di-tert butyl peroxide cetane improver). Remarkably, high gross indicated thermal efficiencies were achieved, reaching 59%, 56%, and 57% for E85-diesel, gasoline-diesel, and gasoline-gasoline+DTBP respectively.Using conditions based on CFD simulations, engine experiments were performed using a heavy-duty test engine and the modeling was further used to explain the experimentally observed results. The experiments confirmed that by optimizing the fuel reactivity based on the specific operating conditions, combustion phasing can be optimized in order to minimize fuel consumption. Additionally, it was found that highly efficient operation (greater than 50% indicated thermal efficiency) could be achieved with all three fuel blending strategies over a wide range of loads. This study showed that, compared to gasoline-diesel, significantly higher quantities of diesel fuel were required to maintain optimal combustion phasing with the E85-diesel fuel blends. This result is due to a combination of the lower reactivity and higher enthalpy of vaporization of ethanol (compared to gasoline) and combustion chemistry effects of ethanol diesel blends. Secondly, the single fuel gasoline-gasoline+DTBP yielded near identical emissions and ISFC results to gasoline-diesel operation. Although the emissions and ISFC of all three strategies were similar, the low temperature heat release (LTHR) were different with all three fuels, and the high temperature heat release (HTHR) was different with E85-diesel blends. Fuel chemistry effects for all three fuels were investigated and their effect on the reactivity gradient was found to be responsible for the combustion differences.