The G protein-coupled receptors (GPCRs) are the largest family of membrane proteins and represent some of the most important pharmaceutical targets. These receptors, encoded by several hundred genes, are activated by a wide variety of endogenous and synthetic ligands. The study of the signal transduction pathways activated by these receptors and the associated mechanisms controlling biological responses have been pivotal in identifying key intracellular molecules for regulating receptor responsiveness. The beta-arrestin proteins, which were initially discovered due to their role in GPCR desensitization, serve equally important roles in regulating internalization and alternative signaling events. This review focuses on the different functions of beta-arrestins to demonstrate how these proteins can help to identify new ligands for GPCRs and how they can serve as a platform for drug discovery.