The challenge of converting sustainable cellulosic biomass into fuels has the opportunity for science and technology making an appreciable national impact in the next 20 years. Bioenergy interest is driven partly by the economics and national security. The effective conversion of lignocellulose into fermentable sugars is the dominant obstacle to cost-effective production of biofuels in sustained quantities capable of impacting U.S. consumption of fossil transportation fuels. Three key questions are: can we do this effectively and efficiently; can we make a significant impact; and can we do this sustainably? The application of new tools from modern system biology has the potential to overcome many current technological and economic challenges. We will discuss the biological approaches being taken to address these questions including the Bioenergy Science Center at ORNL.