Excessive signaling by receptor tyrosine kinases (RTKs) can cause cancer. What molecular mechanisms normally control RTK signaling? Are they defective in tumors? If so, should therapeutics be developed to restore particular regulatory pathways to cancer cells? These questions have been approached through mechanistic studies of a prototypical RTK, the epidermal growth factor receptor (EGFR). EGFR signaling is mediated and regulated by both signaling and trafficking effectors. The amplitude of receptor-proximal signals changes as EGFRs move along the degradative trafficking pathway from the cell surface, to endosomes, and into lysosomes. To optimize therapeutic suppression of receptor oncogenicity, it may be crucial to target EGFRs that are signaling from a specific site in the trafficking pathway. Research suggests that EGFRs at the plasma membrane produce the bulk of the global transcriptional response to EGF. EGFRs localized between the internalization and early endosome fusion stages of the pathway enrich the expression of transcripts associated with cancer. EGFRs at later trafficking checkpoints controlled by the endosomal sorting complex required for transport (ESCRT) complexes II and III do not contribute substantially to the EGFR-mediated transcriptional response. These results suggest that therapeutics targeting the receptors at the earliest stages of degradative trafficking might be most effective.