Ethanol from cellulosic biomass is a promising renewable liquid transportation fuel. Applied research in the area of biomass conversion to ethanol in the last 20 years has answered most of the major challenges on the road to commercialization but, as with any new technology, there is still room for performance improvement. A verified mathematical model was used to examine the most critical biochemical engineering aspects of ethanol production in this study. Extensive simulations of the simultaneous saccharification and fermentation (SSF) of cellulose were conducted to identify the effects of operating conditions, pretreatment effectiveness, microorganism parameters, and enzyme characteristics on ethanol production. The results clearly show that the biomass-enzyme interaction plays a dominant role in determining the performance of SSF in batch and continuous operating modes. In particular, the digestibility of the substrate (as a result of pretreatment) and the cellulase enzyme dosage, specific activity, and composition had a profound effect on ethanol yield. This investigation verified the conclusion that R&D emphasis should be placed on developing more effective pretreatment methods and producing cellulase preparations of high specific activity (low cost per enzyme unit) to realize gains fi om any development of advanced hexose/pentose-fermenting organisms.