Arrestin proteins play a key role in desensitizing G-protein-coupled receptors and re-directing their signaling to alternative pathways. The precise timing of arrestin binding to the receptor and its subsequent dissociation is ensured by its exquisite selectivity for the activated phosphorylated form of the receptor. The interaction between arrestin and the receptor involves the engagement of arrestin sensor sites that discriminate between active and inactive and phosphorylated and unphosphorylated forms of the receptor. This initial interaction is followed by a global conformational rearrangement of the arrestin molecule in the process of its transition into the high-affinity receptor-binding state that brings additional binding sites into action. In this article, we discuss the molecular mechanisms that underlie the sequential multi-site binding that ensures arrestin selectivity for the active phosphoreceptor and high fidelity of signal regulation by arrestin proteins.