This chapter describes the challenges and advances in developing microbes to efficiently deconstruct and ferment plant biomass, focusing on the model bacterium Clostridium phytofermentans. This anaerobic mesophile secretes carbohydratases to depolymerize the heterogeneous polysaccharide matrix that forms plant matter. These polysaccharides, including cellulose, hemicellulose, starch, and pectin, are then fermented to ethanol at high yields. We describe how this microbe was isolated, characterized, and developed into a model laboratory system to study cellulosic fermentation. The complete genome sequence and gene expression profiles of C. phytofermentans give a broad understanding of this microbe's regulatory and metabolic networks and will ultimately lead to a predictive, systems-level understanding of how it ferments biomass. Recently developed methods for the genetic manipulation of C. phytofermentans will enable us to test systems-biology predictions and to develop strains with novel properties. We also discuss experiments that are needed to advance our understanding of how microbes ferment plant biomass.