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Sustainable utilization of non-edible plant biomass is a complex topic that requires an integrated approach that must the nonrenewable resource upon which feedstock production is based, i.e., land. At the same time the engineering of renewable lignocellulose resources for manufacture of low carbon footprint transportation fuels must be based on biorefinery concepts that integrate chemical engineering unit operations to achieve maximal productivity and a diverse bioproduct portfolio based on utilization of cellulose, hemicellulose and lignin. This presentation addresses fundamental and practical matters that must be considered for achieving feedstock security and cost effective biomass processing, as well as impediments to achieving economic production at scale. In particular, the cost of enzymes for cellulose hydrolysis are addressed based on the science of biomass cell wall deconstruction. This talk will describe pathways by which cell wall components - particularly those associated with lignin - inhibit enzyme hydrolysis. While this has proven to a continuing challenge for achieving biomass conversion at economically acceptable enzyme loadings, a fundamental understanding of the mechanisms has evolved. This provides a technical platform for mitigating inhibitory effects in manner that enables major reductions in processing costs. Future developments in biofuel production will also be discussed in the context of sustainable energy and cost-effective conversion of lignocellulose feedstocks to fuels and chemicals.