A mechanistically based kinetic model for the enzymatic hydrolysis of cellulosic biomass has been developed that incorporates the distinct modes of action of cellulases on insoluble cellulose polymer chains. Cellulose depolymerization by an endoglucanase (endoglucanase I, EGI) and an exoglucanase (cellobiohydrolase I, CBHI) is modeled using population-balance equations, which provide a kinetic description of the evolution of a polydisperse distribution of chain lengths. The cellulose substrate is assumed to have enzyme-accessible chains and inaccessible interior chains. EGI is assumed to randomly cleave insoluble cellulose chains. For CBHI, distinct steps for adsorption, complexation, processive hydrolysis, and desorption are included in the mechanistic description. Population-balance models that employ continuous distributions track the evolution of the spectrum of chain lengths, and do not require solving equations for all chemical species present in the reacting mixture, resulting in computationally efficient simulations. The theoretical and mathematical development needed to describe the hydrolysis of insoluble cellulose chains embedded in a solid particle by EGI and CBHI is given in this article (Part I). Results for the time evolution of the distribution of chain sizes are provided for independent and combined enzyme hydrolysis. A companion article (Part II) incorporates this modeling framework to study cellulose conversion processes, specifically, solution kinetics, enzyme inhibition, and cooperative enzymatic action. Biotechnol. Bioeng. 2012; 109:665–675. © 2011 Wiley Periodicals, Inc.