Multivalent lectin-glycan interactions (MLGIs) are widespread and vital for pathogen infection and immune regulation. As monovalent lectin-glycan interactions are often too weak to be bio-active, lectins mostly form multimeric structures with clustered carbohydrate-binding-domains (CRDs), allowing them to bind multivalently with multivalent glycan ligands to enhance affinity and define specificity via spatial matching. The overall MLGI affinity is not only defined by the monovalent affinity, but also the binding mode and glycan valency. In general, a pair of spatially matched MLGI partners may bind simultaneously with each other to form small individual lectin-ligand complexes, giving rise to a great MLGI affinity enhancement due to both favourable binding enthalpy and entropy terms. While those without the perfect spatial-and orientational-matches may crosslink each other to maximize the binding enthalpies, but this often forms large-scale protein-ligand assemblies with relatively low MLGI affinity enhancement due to large entropic penalties. Therefore, understanding the structural and molecular mechanisms of target MLGIs is of great importance, allowing us to design spatial-matched glycoconjugates to target specific MLGIs potently for therapeutical interventions.