A diagram of the EGFR family receptors trafficking to different compartments. The endocytic vesicles carrying EGFR can be transported from the cell surface to several intracellular organelles, including the Golgi apparatus, the ER, the mitochondria, and the nucleus. It has been documented recently that COPI vesicle-mediated retrograde transport from the Golgi to the ER is involved in the EGFR nuclear trafficking. Integral EGFR inserted into the ER membrane is targeted to the INM of the nuclear envelope (NE) through the ONM and NPC via a model of integral trafficking from the ER to the NE transport (INTERNET). The INM-embedded EGFR can be released from the lipid bilayer to the nucleoplasm within the nucleus by the association with the translocon Sec61β located in the INM. In addition to the nuclear import of cell surface EGFR, the internalized EGFR can also be trafficked to the mitochondria; however, the molecular mechanism underlying the cell surface-to-mitochondria trafficking of EGFR remains unclear. Whether the localization of EGFR in the mitochondria is involved in the EGFR trafficking to the Golgi, the ER, and the nucleus has not yet been explored. The scale of the diagram does not reflect the relative sizes of different molecules or subcellular structures. EV, endocytic vesicle; COPI: coat protein complex I; NPC, nuclear pore complex; ER, endoplasmic reticulum; ONM, outer nuclear membrane; INM, inner nuclear membrane.