Current US transportation sector mainly relies on liquid hydrocarbon derived from petroleum and about 60% of the petroleum consumed is from areas where supply may be disturbed by regional instability. This has led to serious concerns on global warming and energy security. To address these issues, numerous alternative energy carriers have been proposed. Among them, second generation biofuel is one of the most promising technologies. Gasification based thermo-chemical conversion can utilize a wide range of biomass wastes and residues and bring flexibility to both feedstock and production sides of a plan. Thus it presents an attractive technical route. In this paper, a flexible feedstock thermo-chemical ethanol production process is investigated. This research focuses mainly on the evaluation of the feasibility of the process through numerical simulation. An existing thermo-chemical ethanol production model developed by NREL has been updated to handle the cases when different biomass feedstock and feedstock combinations are used. It is found that the ethanol yield is positively linear proportional to the feedstock feeding rate, while the total conversion efficiency is negatively proportional to the feeding rate. To demonstrate a feedstock management strategy, a plant located near a major city with a population of 200,000 and above is considered and MSW, corn stover and wood chips are selected as potential feedstock. Simulation results indicate that with wood chips as the backup feedstock the plant can be operated under extreme conditions when corn stover availability is significantly reduced without major equipment modification.