Acting through a number of distinct pathways, many G protein-coupled receptors (GPCRs) activate the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) cascade. Recently, it has been shown that in some cases, clathrin-mediated endocytosis is required for GPCR activation of the ERK/MAPK cascade, whereas in others it is not. Accordingly, we compared ERK activation mediated by a GPCR that does not undergo agonist-stimulated endocytosis, the α 2A adrenergic receptor (α 2A AR), with ERK activation mediated by the β 2 adrenergic receptor (β 2 AR), which is endocytosed. Surprisingly, we found that in COS-7 cells, ERK activation by the α 2A AR, like that mediated by both the β 2 AR and the epidermal growth factor receptor (EGFR), is sensitive to mechanistically distinct inhibitors of clathrin-mediated endocytosis, including monodansylcadaverine, a mutant dynamin I, and a mutant β -arrestin 1. Moreover, we determined that, as has been shown for many other GPCRs, both α 2A and β 2 AR-mediated ERK activation involves transactivation of the EGFR. Using confocal immunofluorescence microscopy, we found that stimulation of the β 2 AR, the α 2A AR, or the EGFR each results in internalization of a green fluorescent protein-tagged EGFR. Although β 2 AR stimulation leads to redistribution of both the β 2 AR and EGFR, activation of the α 2A AR leads to redistribution of the EGFR but the α 2A AR remains on the plasma membrane. These findings separate GPCR endocytosis from the requirement for clathrin-mediated endocytosis in EGFR transactivation-mediated ERK activation and suggest that it is the receptor tyrosine kinase or another downstream effector that must engage the endocytic machinery.