Crop residues are considered to be an important lignocellulosic feedstock for future biofuel production. Harvesting crop residues, however, could lead to serious soil degradation and loss of productivity. Our objective was to evaluate trade-offs associated with harvesting residues including impacts on soil quality, soil organic C and nutrient removal. We used cropping systems data collected at 369 geo-referenced points on the 37-ha Washington State University Cook Agronomy Farm to aid our evaluation. Site-specific field estimates of lignocellulosic ethanol production from winter wheat residues ranged from 813 to 1767 L/ha and averaged 1356 L/ha suggesting that targeted harvesting of crop residues may be an important consideration. Harvesting winter wheat residues reduced remaining residue C inputs to levels below that required to maintain soil organic C under conventional tillage practices. This occurred as a function of both residue removal and the inclusion of a low residue producing spring pea crop in rotation with wheat. Harvesting winter wheat residues under conventional tillage resulted in negative Soil Conditioning Indices (SCI) throughout the field. In contrast, SCI’s under no-till were positive despite residue harvesting. Estimated value of nutrients (N, P, K, S) removed in harvested wheat residue was $13.71/metric ton. In high residue producing areas of the field, the estimated value of harvested residue in fertilizer replacement dollars was over $25/ha. We concluded that substantial trade-offs exist in harvesting wheat straw for biofuel, that trade-offs should be evaluated on a site-specific basis, and that support practices such as crop rotation, reduced tillage and site-specific nutrient management need to be considered if residue harvest is to be a sustainable option.