An attractive operation strategy for the enzymatic hydrolysis of lignocellulosics results from dividing the process into three stages with complementary goals: continuous enzyme adsorption at low-solids loading (5% w/w) with recycling of the liquid phase; continuous liquefaction at high-solids content (up to 20% w/w); and, finally, continuous or semicontinuous hydrolysis with supplementation of fresh enzymes. This paper presents a detailed modeling and simulation framework for the aforementioned operation strategies. The limiting micromixing situations of macrofluid and microfluid are used to predict conversions. The adsorption and liquefaction stages are modeled as a continuous stirred tank and a plug flow reactor, respectively. Two alternatives for the third stage are studied: a train of five cascading stirred tanks and a battery of batch reactors in parallel. Simulation results show that glucose concentrations greater than 100 g L-1 could be reached with both of the alternatives for the third stage.