Endocytic trafficking of G –protein-coupled receptors (GPCRs) to lysosomes is an important mechanism promoting receptor downregulation following prolonged agonist stimulation. It has been reported that a number of membrane proteins and some GPCRs require covalent modification by ubiquitin moieties in order to undergo efficient endocytic sorting to lysosomes (1). This sorting process is mediated by ubiquitin-dependent protein interactions directing endocytosed receptors to an endosome-associated sorting machine composed of a conserved set of ‘ESCRT’ proteins (2). While this mechanism is well supported in studies of receptor sorting in budding yeast, we have previously shown that one mammalian GPCR, the mouse delta opioid receptor, undergoes efficient ESCRT-dependent sorting to lysosomes without requiring receptor ubiquitination (3, 4). Here we demonstrate that the same is true for the human β2 adrenergic receptor (β2AR). Using stably transfected HEK 293 cells expressing epitope-tagged receptors we demonstrate that a mutant β2AR lacking all lysine residues undergoes efficient agonist induced lysosomal proteolysis, in the absence of direct ubiquitination. Furthermore, we establish a critical role of a C-terminal ‘recycling sequence’ in controlling β2AR sorting to lysosomes in the absence of receptor ubiquitination. Moreover, we show that ubiquitination-independent lysosomal sorting of the β2AR, like ubiquitination-directed sorting of other membrane cargo, requires the ‘core’ ESCRT protein Vps4- as well as the ESCRT-associating protein HRS. Finally, we identify a late stage in the process of β2AR degradation, which is not dependent on lysosomal sorting or the onset of receptor proteolysis and can reconcile the present results with previous evidence for ubiquitination-dependent lysosomal sorting of the β2AR. Together these results reveal a fundamental and hitherto unappreciated cellular mechanism of GPCR regulation, which applies to the ‘prototypic’ β2AR and thus may play a widespread role in controlling GPCR signaling in mammals.