A detailed mechanistic model of enzymatic cellulose hydrolysis has been developed. The behavior of individual cellulase enzymes and parameters describing the cellulose surface properties are included. Results obtained for individual enzymes (T. reesei endoglucanase 2 and cellobiohydrolase I) and systems with both enzymes present are compared with experimental literature data. The model was sensitive to cellulase-accessible surface area; the EG2–CBHI synergy observed experimentally was only predicted at a sufficiently high cellulose surface area. Enzyme crowding, which is more apparent at low surface areas, resulted in differences between predicted and experimental rates of hydrolysis. Model predictions also indicated that the observed decrease in hydrolysis rates following the initial rate of rapid hydrolysis is not solely caused by product inhibition and/or thermal deactivation. Surface heterogeneities, which are not accounted for in this work, may play a role in decreasing the hydrolysis rate. The importance of separating the enzyme adsorption and complexation steps is illustrated by the model's sensitivity to the rate of formation of enzyme–substrate complexes on the cellulose surface. Biotechnol. Bioeng. 2010;107: 37–51. © 2010 Wiley Periodicals, Inc.