Large water-soluble anions with chaotropic character display surprisingly strong supramolecular interactions in water, for example, with macrocyclic receptors, polymers, biomembranes, and other hydrophobic cavities and interfaces. The high affinity is traced back to a hitherto underestimated driving force, the chaotropic effect, which is orthogonal to the common hydrophobic effect. This review focuses on the binding of large anions with water-soluble macrocyclic hosts, including cyclodextrins, cucurbiturils, bambusurils, biotinurils, and other organic receptors. The high affinity of large anions to molecular receptors has been implemented in several lines of new applications, which are highlighted herein.