The sustainable development of biofuels and biochemicals in lignocellulosic biorefineries is a critical focus in the search for alternatives to fossil fuels, which are major contributors to greenhouse gas emissions. In this context, bioreactor configuration plays a pivotal role in establishing efficient and scalable production processes. Recent studies have explored key strategies for optimizing bioreactor configurations, with particular emphasis on submerged fermentation systems and enzymatic hydrolysis step. Critical parameters such as temperature control, pH, aeration, and agitation have been extensively analyzed for their impact on productivity in the conversion of renewable raw materials into biomolecules of industrial interest. Among the established approaches for obtaining biochemicals, second-generation ethanol (2G) production relies on strategies such as Simultaneous Saccharification and Fermentation (SSF) and Simultaneous Saccharification and Co-Fermentation (SSCF). These strategies may employ either single or separate reactors, sometimes integrated with membrane systems to enhance process efficiency. Simultaneous conversion of sugars into ethanol or other products minimizes glucose accumulation, which could otherwise inhibit cellulolytic enzyme activity. Furthermore, combining saccharification and fermentation or co-fermentation in a single reactor eliminates the need for the sequential addition of microorganisms and enzymes in separate equipment, thereby improving overall process efficiency. Additionally, the ability to utilize both five-carbon (C5) and six-carbon (C6) sugars significantly enhances the efficiency of biomass conversion into biofuels in co-fermentation processes. The integration of simultaneous processing steps also reduces total production time, leading to increased productivity. An alternative strategy is the consolidated bioprocess (CBP), which leverages microbial strains, natural or genetically engineered, which possess the ability to produce the enzymes required for biomass hydrolysis while simultaneously carrying out fermentation within the same system, streamlining the entire conversion process. Various reactor configurations, including membrane-integrated ones and interconnected columns, can be implemented to optimize SSF/SSCF and CBP, depending on specific process requirements. Furthermore, development of these bioprocesses in different bioreactor systems can improve yields and productivities in biorefineries. Actually, tailoring bioreactor configurations to the specific characteristics of the process configuration is required to ensure maximum efficiency and economic feasibility. This chapter provides a discussion of the main aspects of bioreactor design for lignocellulosic biorefineries, highlighting the crucial role of well-engineered and properly operated equipment with optimized process parameters. Special attention is given to key strategies, including SSF, SSCF, and CBP, with a focus on their contributions to enabling the efficient and sustainable production of biofuels and biochemicals.