Advanced engine technologies will play a central role in achieving future greenhouse gas (GHG) emissions targets for light-duty vehicles. However, these technologies will place greater emphasis on optimizing the engine and fuel as a synergistic system, since many technologies will require higher octane gasolines to realize their full social and environmental benefits. The most extreme example of a synergistic engine-fuel system is the Octane on-Demand concept. This technology platform makes use of an oil-derived fuel at low and intermediate loads where the octane requirement of the engine is comparatively low, while a second high octane fuel is introduced at higher loads to suppress knock. This paper presents the first comprehensive study of vehicle fuel economy and well-to-wheel GHG emissions for the Octane-on-Demand concept with respect to a regular grade E10 gasoline (RON 93) and a high octane E30 gasoline (RON 101). Experimental fuel consumption maps are first used to evaluate the drive cycle fuel economy and GHG emissions for a light-duty vehicle equipped with two alternative powertrains. The upstream GHG emissions arising from the production of the fuels are then quantified, with consequent uncertainties assessed using Monte Carlo analysis based on probability distribution functions for critical input parameters. The results demonstrate that the Octane-on-Demand concept used in conjunction with either methanol or ethanol generally provides comparable well-to-wheel GHG emissions to the high octane E30 gasoline, with up to a 10% improvement in the vehicle fuel economy. The use of a non-traditional engine calibration strategy that maximizes the trade-off between thermal efficiency and fuel energy density also enables the amount of high octane fuel required to suppress knock to be reduced significantly. This increases the distance that the vehicle can be driven before the secondary tank requires refueling by a considerable margin, but comes at the expense of marginally higher well-to-wheel GHG emissions than could otherwise be achieved. These findings are shown to be largely insensitive to uncertainties in the upstream fuel production GHG emissions, with the exception of the land use change (LUC) for bioethanol. Overall, this study has implications for the design of engine-fuel systems for future light-duty vehicles.