Agricultural by-products represent the feedstock of interest for bioconversion into alternative fuels such as cellulosic ethanol. In Nature, several microorganisms have evolved the ability to hydrolyze components of the plant into fermentable monomeric sugars. The enzymes encoded in the genomes of cellulolytic bacteria are often modular in nature and consist of multiple catalytic domains fused to targeting modules called carbohydrate-binding domains. Bio-informatic and preliminary biochemical analyses on these genes have fostered the notion that these different catalytic activities are independent and represent an “assembly line” approach to polysaccharide analysis. Here, we present detailed biochemical and structural analysis of representative multi-component systems that demonstrate that these multiple catalytic domains represent single structural units that facilitate cross talk amongst the different activities. Our high-resolution structural analyses of tandem carbohydrate domains of the T. polysaccharolyticum manA gene bound to cognate ligands and of the multi-functional xylanase-esterase from C. thermocellum represent examples in which regions that link the multiple activities play a structural and functional role in the interplay between the domains.