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Virtually all currently used therapeutic agents are small molecules, largely because the development and delivery of small molecule drugs is relatively straightforward. Small molecules have serious limitations: drugs of this type can be fairly good enzyme inhibitors, receptor ligands, or allosteric modulators. However, most cellular functions are mediated by protein interactions with other proteins, and targeting protein-protein interactions by small molecules presents challenges that are unlikely to be overcome with these compounds as the only tools. Recent advances in gene delivery techniques and characterization of cell type-specific promoters open the prospect of using reengineered signaling-biased proteins as next-generation therapeutics. The first steps in targeted engineering of proteins with desired functional characteristics look very promising. As quintessential scaffolds that act strictly via interactions with other proteins in the cell, arrestins represent a perfect model for the development of these novel therapeutic agents with enormous potential: custom-designed signaling proteins will allow us to tell the cell what to do and when to do it in a way it cannot disobey.