This chapter presents an overview of the challenges associated with integrating yeast fermentation into cellulosic biofuel processes, as well as the approaches that might overcome these challenges. The chapter first introduces the design considerations for first-generation ethanol fermentation processes using sugar cane and corn as feedstocks, with an emphasis on process constraints and operation strategies. The chapter then explores methods for improving yield, titer, productivity, and economics. These processing methods illustrate the challenges posed by the fermentation of ethanol from lignocellulose hydrolyzates, especially the differences in process constraints for high-productivity, high-product titer operations. Finally, the chapter discusses an example of aerobic seed cultivation of yeast using a hydrolyzate of dilute acid-hydrolyzed softwood hemicellulose.