Design considerations for continuous conversion of biomass to ethanol using the simultaneous saccharification and fermentation (SSF) process are discussed. A previously presented and verified modeling approach is extended to describe advanced solid-substrate reactor systems incorporating solids and enzyme retention, and reaction in CSTR cascades. A single solids retaining CSTR has predicted advantages over a batch process at low-residence time and conversion. The predicted performance of a cascade of CSTR reactors for SSF approaches that-of the batch system, whereas a cascade system with differential retention of solids with respect to the aqueous phase (solids residence time = 1.5 times the liquid residence time) is predicted to allow a 47% decrease in overall reactor volume relative to a batch system at high conversion (90% cellulose utilization). Further benefits are anticipated because of the effects of substrate classification in nonwell-mixed reactor configurations. Apparatus for laboratory-scale experimentation using solid substrates is presented, along with progress toward experimental verification of the reactor concepts proposed. In addition to predicting bioreactor productivity, the modeling was used to examine ethanol tolerance. In contrast to the approximately linear inhibition trend observed for soluble substrates, the ratio of dilution rates necessary to achieve a fixed conversion in the absence and presence of inhibition is essentially unity until the maximum growth rate is approached, and falls precipitously thereafter. Implications of this and other simulation results for the bioreactor design are discussed.