Animals express hundreds of different G protein-coupled receptors (GPCRs), most of which are regulated by phosphorylation and specific binding of arrestin proteins to active phosphorylated receptors. This makes arrestin binding to GPCRs one of the most common protein–protein interactions in cell signalling. This chapter describes known molecular mechanisms of this interaction, which involves an “induced fit” that goes both ways. We focus on the receptor-induced rearrangements in arrestins and arrestin-induced changes in receptor conformation. While arrestin-mediated signalling has been extensively described at phenomenological level, exact structural changes in both proteins that determine functional consequences of arrestin binding to the receptor in the cell remain to be elucidated. Arrestin conformation dramatically affects its interactions with many non-receptor binding partners. Since these interactions mediate G protein-independent GPCR signalling, the elucidation of molecular mechanisms involved is necessary for the understanding of biological functions of GPCRs and arrestins. This information also lays the foundation for the design of novel molecular tools for targeted therapeutic intervention in numerous disorders associated with inherited and acquired errors in cell signalling.