The bioactive activities of the phlorotannins depend not only on their structure, composition, conformation, and quantity but also on their intermolecular interactions. Hence, phlorotannins like terrestrial tannins interact with macromolecules, i.e., proteins and polysaccharides. This chapter summarizes the current state of knowledge on both the internal and external factors that influence phlorotannins macromolecules interactions, and introduces the different mechanisms involved in these interactions.