Glycan-binding proteins mediate diverse aspects of cell biology including pathogen recognition of host cells, cell trafficking, endocytosis and modulation of cell signaling. This is accomplished despite the intrinsic low affinity for their ligands through multivalent interactions that increase effective affinity and adhesive force. Recent successes in the rational design of high-affinity ligands for glycan-binding proteins offer the promise to create well-defined tools for exploring the structure and functions of this class of receptors.