Increasing numbers of standards for emissions and fuel economy drive the need to downsize spark ignition internal combustion engines. To accommodate this change while reducing engine knock, fuels with higher octane numbers are needed. However, studies have shown that octane requirements are not uniform across the vehicle drive cycle, leading to inefficient use of the high-octane fuel components. One approach shown to substantially increase fuel economy through the efficient use of high-octane fuel components is a dual-fuel solution called octane-on-demand. Octane-on-demand supplies fuel that has the required octane rating, as dictated by the engine torque demands, by delivering the proper ratio of high- and low-octane fuels. Barriers associated with introducing two fuels in the marketplace for an octane-on-demand approach can be overcome using an onboard separation system to separate a single fuel, such as a market E10 gasoline, into a high-octane oxygenate, such as ethanol, and a lower-octane base fuel. Onboard separation systems currently under evaluation rely on pervaporation membranes, which lose efficiency as the oxygenate is removed, leading to inefficient use of this valuable fuel component. Here, we present liquid-solid and liquid-liquid chemical separation strategies that may provide advantages over membrane separation. This paper introduces applications of tailored chemical reactions, solid sorbent materials, and ionic liquids that are shown to have a high oxygenate recovery and utility beyond ethanol to potential future oxygenate additives, such as isomers of butanol.