β-Adrenergic receptors (βARs), prototypical G-protein-coupled receptors, play a pivotal role in regulating neuronal and cardiovascular responses to catecholamines during stress. Agonist-induced receptor endocytosis is traditionally considered as a primary mechanism to turn off the receptor signaling (or receptor desensitization). However, recent progress suggests that intracellular trafficking of βAR presents a mean to translocate receptor signaling machinery to intracellular organelles/compartments while terminating the signaling at the cell surface. Moreover, the apparent multidimensionality of ligand efficacy in space and time in a cell has forecasted exciting pathophysiological implications, which are just beginning to be explored. As we begin to understand how these pathways impact downstream cellular programs, this will have significant implications for a number of pathophysiological conditions in heart and other systems, that in turn open up new therapeutic opportunities.