Lectin-glycan interactions (LGIs) are widespread and play a pivotal role in biology. As individual LGIs are intrinsically weak, and hence mostly biologically inactive, most lectins form multimeric structures, allowing them to bind multivalently with multivalent glycans to enhance affinity and form biologically relevant interactions. In fact, multivalent LGIs (MLGIs) can offer an incredibly wide range of binding affinities with exquisite selectivity from a relatively small number of weak individual LGIs, to satisfy the needs of biology. In this regard, matching the spatial and orientation between multivalent binding partners is key to high binding affinity and selectivity. Moreover, binding of specific secreted and/or cell membrane bound lectins with pathogen associated glycan patterns is critical in pathogen recognition and activation of host immune defense against infection. Unfortunately, dysregulated, constant immune activation can lead to persistent inflammation and tissue death. Besides this, MLGIs are also exploited by pathogens (e.g. viruses, bacteria and fungi) and cancer cells to suppress host immune activation and evade immune surveillance in order to facilitate infection and/or cancer development. Therefore, revealing the biophysical and structural details of relevant MLGIs is of great importance, not only for fundamental mechanistic studies but also for the development of effective therapeutic interventions against specific MLGIs.