The development of sustainable biotechnological processes is important for advancements in production of renewable chemicals, biofuels, and materials. A significant challenge is handling high biomass total solids (TS) loading, which is significant to enhance the cost-effectiveness and efficiency of biorefineries. Further, advancements in biomass pretreatment methods, such as hydrodynamic cavitation, that are employed to disrupt the complex structure of biomass, facilitating enzymatic hydrolysis and improving overall process yields, have shown promising results. Efficient pretreatment, novel enzyme evolution and hydrolysis using high TS concentration coupled with process intensification approaches i.e. simultaneous saccharification and co-fermentation (SSCF), simultaneous saccharification and fermentation (SSF), and consolidated bioprocessing (CBP) could be revolutionary in the biomass refineries. There are some key factors influencing reactor performance, such as biomass characteristics, mass transfer, enzyme characteristics, rheology, and heat transfer. These factors are critical in overcoming the challenges associated with high TS loading, including increased viscosity, microorganism selection and reduced mixing efficiency. This review highlights such critical factors when dealing with high biomass loading, by presenting strategies and reactor configurations to improve the scalability and economic viability of lignocellulosic biorefineries.