G protein-coupled receptors are 7 transmembrane domain (7TM) proteins that mediate the signaling of a multitude of stimuli in nature. Although 40-60% of all marketed drugs target this class of receptor proteins, evidence suggest that they may still represent a rich source of untapped opportunities. Classically, 7TM receptors mediate their physiological effects through activation of G proteins however, that action is invariably accompanied my mechanisms that limit their G protein-dependent signaling activity with time. One of these mechanisms is the agonist-dependent phosphorylation of receptor by a family of receptor kinases (GRK) followed by the interaction of the phosphorylated receptor with an arrestin molecule. This interaction not only limits the G protein-dependent signaling but also initiates a series of events that lead to the internalization, dephosphorylation and plasma membrane recycling of the receptor as well as the elaboration of new signaling pathways not previously associated with 7TM receptors. The development of a real time/single cell assay based on the ability of arrestin molecules to translocate to and interact with the activated receptor (Barak et al, 1997) has provided a convenient means to interrogate these mechanisms not only for the purpose of lead discovery but also for the elucidation of new biochemical paradigms. These new paradigms may represent new ways in which these 7TM-mediated physiological responses can targeted for therapeutic potentials.