It is now well established that G-protein coupled receptors (GPCRs) are hyper-phosphorylated following agonist occupation usually at serine and threonine residues contained on the third intracellular loop and C-terminal tail. After some 2 decades of intensive research, the nature of protein kinases involved in this process together with the signalling consequences of receptor phosphorylation has been firmly established. The major challenge that the field currently faces is placing all this information within a physiological context and determining to what extent does phosphoregulation of GPCRs impact on whole animal responses. In this chapter, we address this issue by describing how GPCR phosphorylation might vary depending on the cell type in which the receptor is expressed and how this might be employed to drive selective regulation of physiological responses.