β-arrestin1 and β-arrestin2 were initially identified by sequence homology to visual arrestins and by their ability to bind to and inactivate signaling of the beta-2-adrenergic receptor in a process known as desensitization. While the role of β-arrestins in desensitization has been known for some time, more recent evidence has revealed that β-arrestins are multifunctional scaffolding proteins that are involved in numerous aspects of G protein-coupled receptor (GPCR) signaling. Interestingly, exciting new data shows that β-arrestins can mediate signaling in their own right independent of classical second messenger mediated signaling, and that this β-arrestin-mediated signaling may be cardioprotective. Identifying novel ligands for GPCRs that can block G protein-mediated signaling while simultaneously promoting β-arrestin-mediated signaling could provide powerful new therapies for cardiac disease.