Until now, most efforts to improve monosaccharide production from biomass through pretreatment and enzymatic hydrolysis have used empirical optimization rather than employing a rational design process guided by a theory-based modeling framework. For such an approach to be successful a modeling framework that captures the key mechanisms governing the relationship between pretreatment and enzymatic hydrolysis must be developed. In this study, we propose a pore-hindered diffusion and kinetic model for enzymatic hydrolysis of biomass. When compared to data available in the literature, this model accurately predicts the well-known dependence of initial cellulose hydrolysis rates on surface area available to a cellulase-size molecule. Modeling results suggest that, for particles smaller than 5 × 10−3 cm, a key rate-limiting step is the exposure of previously unexposed cellulose occurring after cellulose on the surface has hydrolyzed, rather than binding or diffusion. However, for larger particles, according to the model, diffusion plays a more significant role. Therefore, the proposed model can be used to design experiments that produce results that are either affected or unaffected by diffusion. Finally, by using pore size distribution data to predict the biomass fraction that is accessible to degradation, this model can be used to predict cellulose hydrolysis with time using only pore size distribution and initial composition data