Data will be presented from a comprehensive recent study aimed at evaluating the cumulative and relative impact of "multiple levers" to overcome the lignocellulose recalcitrance barrier, including choice of biocatalyst and feedstock, genetically modified plants and less recalcitrant natural variants, and several non-biological approaches to assist the deconstruction process. Anaerobic thermophilic bacteria are found to be decisively more effective than industry-standard fungal cellulase at solubilizing cellulosic biomass under a broad range of conditions. However even the best plant cell wall-solubilizing biocatalysts require some assistance in order for lignocellulose to be processed with high yields in a reasonable amount of time. As an alternative to thermochemical pretreatment, we are investigating physical disruption once fermentation is initiated – termed cotreatment. Results presented include: a) demonstration of fermentation in the presence of physical disruption at an intensity sufficient to substantially increase lignocellulose solubilization, b) high extents of solubilization comparable to conventional pretreatment, c) lignin residues with less modification than result from thermochemical pretreatment. Taking advantage of the outstanding capability of thermophilic anaerobic bacteria to ferment cellulosic biomass without added enzymes requires that metabolic engineering tools be developed and applied to these organisms in order to bring product yields and titers to industrially acceptable levels. Recent progress will be described involving the cellulose-fermenting Clostridium thermocellum as well as hemicellulose-utilizing thermophiles such as Thermoanaerobacterium saccharolyticum. Technoeconomic analysis indicates potential for 8-fold shorter payback period and feasibility at several-fold smaller scale as compared to current technology using the fungal cellulase-thermochemical pretreatment paradigm.