The epidermal growth factor receptor (EGFR) is a key regulator of epithelial tissue development and homeostasis. In pathological settings, particularly in lung, breast cancer, and glioblastoma, EGFR plays a crucial role in tumorigenesis, often due to amplification, point mutations, or transcriptional upregulation. The canonical EGFR signaling pathway involves ligand-induced receptor dimerization, kinase activation, and subsequent signaling through multiple pathways, including Ras/MAPK, PI3K/AKT, and PLC/ PKC. However, recent studies have revealed non-canonical functions of EGFR, such as in stress-induced trafficking, autophagy, and energy metabolism. These functions are often induced by cellular and environmental stresses and contribute to cancer cell survival and resistance to therapy. The article reviews the canonical and non-canonical EGFR signaling pathways, focusing on their regulation by endocytosis and subversion in human tumors. It also discusses the emerging role of EGFR in stress-induced trafficking, autophagy, and energy metabolism, highlighting potential therapeutic applications. The authors emphasize the importance of understanding how membrane trafficking influences the efficacy of EGFR-targeted therapies to improve treatment outcomes and delay resistance.The epidermal growth factor receptor (EGFR) is a key regulator of epithelial tissue development and homeostasis. In pathological settings, particularly in lung, breast cancer, and glioblastoma, EGFR plays a crucial role in tumorigenesis, often due to amplification, point mutations, or transcriptional upregulation. The canonical EGFR signaling pathway involves ligand-induced receptor dimerization, kinase activation, and subsequent signaling through multiple pathways, including Ras/MAPK, PI3K/AKT, and PLC/ PKC. However, recent studies have revealed non-canonical functions of EGFR, such as in stress-induced trafficking, autophagy, and energy metabolism. These functions are often induced by cellular and environmental stresses and contribute to cancer cell survival and resistance to therapy. The article reviews the canonical and non-canonical EGFR signaling pathways, focusing on their regulation by endocytosis and subversion in human tumors. It also discusses the emerging role of EGFR in stress-induced trafficking, autophagy, and energy metabolism, highlighting potential therapeutic applications. The authors emphasize the importance of understanding how membrane trafficking influences the efficacy of EGFR-targeted therapies to improve treatment outcomes and delay resistance.