G-protein-coupled receptors (GPCRs) are the primary interaction partners for arrestins. The visual arrestins, arrestin1 and arrestin4, physiologically bind to only very few receptors, i.e., rhodopsin and the color opsins, respectively. In contrast, the ubiquitously expressed nonvisual variants β-arrestin1 and 2 bind to a large number of receptors in a fairly nonspecific manner. This binding requires two triggers, agonist activation and receptor phosphorylation by a G-protein-coupled receptor kinase (GRK). These two triggers are mediated by two different regions of the arrestins, the "phosphorylation sensor" in the core of the protein and a less well-defined "activation sensor." Binding appears to occur mostly in a 1:1 stoichiometry, involving the N-terminal domain of GPCRs, but in addition a second GPCR may loosely bind to the C-terminal domain when active receptors are abundant.Arrestin binding initially uncouples GPCRs from their G-proteins. It stabilizes receptors in an active conformation and also induces a conformational change in the arrestins that involves a rotation of the two domains relative to each other plus changes in the polar core. This conformational change appears to permit the interaction with further downstream proteins. The latter interaction, demonstrated mostly for β-arrestins, triggers receptor internalization as well as a number of nonclassical signaling pathways.Open questions concern the exact stoichiometry of the interaction, possible specificity with regard to the type of agonist and of GRK involved, selective regulation of downstream signaling (=biased signaling), and the options to use these mechanisms as therapeutic targets.