Industrial biotechnology is the conversion of biomass via biocatalysis, microbial fermentation, or cell culture to produce chemicals, materials, and/or energy. Industrial biotechnology processes aim to be cost-competitive, environmentally favorable, and self-sustaining compared to their petrochemical equivalents. Common to all processes for the production of energy, commodity, added value, or fine chemicals is that raw materials comprise the most significant cost fraction, particularly as operating efficiencies increase through practice and improving technologies. Today, crude petroleum represents the dominant raw material for the energy and chemical sectors worldwide. Within the last 5 years petroleum prices, stability, and supply have increased, decreased, and been threatened, respectively, driving a renewed interest across academic, government, and corporate centers to utilize biomass as an alternative raw material. Specifically, bio-based ethanol as an alternative biofuel has emerged as the single largest biotechnology commodity, with close to 46 billion L produced worldwide in 2005. Bioethanol is a leading example of how systems biology tools have significantly enhanced metabolic engineering, inverse metabolic engineering, and protein and enzyme engineering strategies. This enhancement stems from method development for measurement, analysis, and data integration of functional genomics, including the transcriptome, proteome, metabolome, and fluxome. This review will show that future industrial biotechnology process development will benefit tremendously from the precedent set by bioethanol - that enabling technologies (e.g., systems biology tools) coupled with favorable economic and socio-political driving forces do yield profitable, sustainable, and environmentally responsible processes. Biofuel will continue to be the keystone of any industrial biotechnology-based economy whereby biorefineries leverage common raw materials and unit operations to integrate diverse processes to produce demand-driven product portfolios.