To better understand the mechanism of enzymatic hydrolysis of cellulose, we applied a restart protocol to explore how cellulose reactivity changed and the interaction of cellulose with major cellulase components over the course of enzymatic hydrolysis.  This approach allowed us to accurately monitor the hydrolysis rate of partially converted cellulose over the time course of substrate digestion excluding the impact of cellulase changes.  In this study, the effect of enzyme-substrate interactions on reaction rates was investigated using purified key cellulase components (i.e., CBHI, EGI, and/or EGII) from wild type Trichoderma reesei. The synergism of these key components was studied by comparing the interrupted enzymatic hydrolysis of pure cellulose using the restart protocol with uninterrupted hydrolysis by individual key cellulase components and their mixtures. For the first time, our results showed the dynamic profiles of adsorption, sugar release rates, and oligosaccharide (DP up to 7)  yields from hydrolysis by individual enzyme components and their synergism over the hydrolysis time course during interrupted enzymatic hydrolysis of Avicel. A new model of enzymatic hydrolysis of cellulose regarding cellulose reactivity, oligomer distribution, effective enzyme binding capacity, and equilibration of depolymerization limiting factors will also be discussed.