Control of the monomer sequence in polymers is extraordinarily difficult by chemical synthesis, though Nature routinely exerts such control, including in the biosynthesis of polysaccharides. This inability has prevented us from being able to match the exquisite structure activity control exhibited in biosynthesis of bioactive natural polysaccharides. We here address a powerful approach, whereby enzyme-catalyzed polymerization of properly modified building blocks is introduced as a simple route affording polysaccharides with controlled sequence and functionalization pattern. Targeting cellulose as a versatile scaffold for novel biomaterials, we describe the preparation of a perfectly alternating polysaccharide with repeat unit 6'-azido-6'-deoxycellobiose by a glycosynthase-catalyzed polymerization using the Humicola insolens cellulase Ce17B E197A mutant, and its further functionalization to give novel modified cellulose derivatives with a regular substitution pattern.