Ligand binding to the epidermal growth factor receptor (EGFR) on the cell surface activates the extracellular signal-regulated kinase (ERK) cascade. Activated, ligand-bound receptors are internalized, and this process may contribute to termination of signaling or enable signaling from intracellular sites. ESCRT (endosomal sorting complex required for transport) complexes may contribute to termination of signaling by sorting receptors into intraluminal vesicles of multivesicular endosomes from which the receptors continue into lysosomes for degradation. We showed that depletion of ESCRTs, which causes the retention of the EGFR in endosomes, increased the activation of the EGFR and its downstream kinases but had little effect on the overall profile and amplitude of the EGF-induced transcriptional response. In contrast, interfering with receptor endocytosis or ubiquitination to keep the EGFR at the cell surface stimulated increases in the abundance of many EGF-induced transcripts, similar to those induced by EGFR overexpression. We also found that the complete EGF transcriptional program was rapidly activated after ligand binding to the receptor. We conclude that the transcriptional response is elicited primarily by receptor molecules at the cell surface.