: This chapter addresses the update progress in bioprocess engineering. In addition to an overview of the theory of multi-scale analysis for fermentation process, examples of scale-up practice combining microbial physiological parameters with bioreactor fluid dynamics are also described. Furthermore, the methodology for process optimization and bioreactor scale-up by integrating fluid dynamics with biokinetics is highlighted. In addition to a short review of the heterogeneous environment in large-scale bioreactor and its effect, a scale-down strategy for investigating this issue is addressed. Mathematical models and simulation methodology for integrating flow field in the reactor and microbial kinetics response are described. Finally, a comprehensive discussion on the advantages and challenges of the model-driven scale-up method is given at the end of this chapter.