In this work, different process configurations were studied, particularly Simultaneous Saccharification and Fermentation (SSF) and Separate Hydrolysis and Fermentation (SHF). The factors determining the selection of the process layout were investigated in details, including the high inhibitors from high solid loading, enzyme mixture, and pretreatment severity and methods, et al. It is revealed that in the situation of the high solid loading and high inhibitors, the better enzyme performance and a potentially better overall process configuration cab be achieved by the dedicated hydrolysis separated from the fermentation. Meanwhile, the choice of the process layout varies with the performance of the enzymes, and the better process layout can be shifted with different enzyme cocktails. The severities of pretreatment and different pretreatment methods may also change the process layout to reflect best cost-efficient solution in ligocellulosic ethanol due to the generation of the different inhibitor compounds.