Widely blended in the transportation fuels, biofuels have been generally regarded as indispensable components in the U.S. national energy portfolio. Although the current production of cellulosic biofuels has been staggering at pilot scales, it is expected that large-scale cultivation of cellulosic biofuel crops may occur when techniques for cost-effective bioconversion of lignocellulosic biomass to ethanol are available. However, it is still unclear if enough land is in existence to accommodate potential large-scale lignocellulosic crops development without negative effects on the environment and food market. The appropriate land use for the next-generation biofuel crops should be planned and allocated in a manner that the competitive use of land dedicated to food and energy production and other side effects could be minimized. This research proposes an approach of identifying the potential available land for planting switchgrass in the U.S. Midwest using a GIS-based multi-criteria analysis that combines soil and water constraint factors. The results showed that land areas of approximately 13.6 million ha are unsuitable for profitable food crops but available for switchgrass cultivation in 7 U.S. Great Plains states. The findings can assist decision-makers in formulating land use policies and related environmental management strategies.