The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that plays a critical role in epithelial cell physiology. In cancer, EGFR is a driver of tumorigenesis, often amplified or mutated. Its activation can lead to uncontrolled cell proliferation and resistance to therapy. While the canonical EGFR signaling pathway is well understood, recent studies have revealed noncanonical functions of EGFR in stress-induced trafficking, autophagy, and energy metabolism. These functions are increasingly recognized as important in cancer progression and resistance. EGFR signaling is regulated by endocytosis, which influences its trafficking and signaling outcomes. The EGFR can undergo clathrin-mediated endocytosis (CME) and nonclathrin endocytosis (NCE), with NCE being more active at higher EGF concentrations. EGFR trafficking is also influenced by cellular stress, such as UV radiation, hypoxia, and oxidative stress, which can trigger ligand-independent EGFR internalization and signaling. These stress-induced pathways can promote cancer cell survival and resistance to therapy. EGFR also plays a role in autophagy, which is critical for cellular homeostasis. In nutrient-rich conditions, EGFR inhibits autophagy by phosphorylating Beclin-1, while in serum-starved conditions, it promotes autophagy. EGFR can also localize to the nucleus and mitochondria, where it influences cell survival, metabolism, and resistance to apoptosis. EGFR signaling is involved in metabolic reprogramming, including aerobic glycolysis and fatty acid synthesis, which support cancer cell proliferation. EGFR-targeted therapies, such as monoclonal antibodies and small-molecule inhibitors, are used in cancer treatment. However, resistance often develops due to EGFR mutations, alterations in other kinases, or feedback loops that counteract EGFR inhibition. Understanding the role of membrane trafficking in EGFR signaling could improve the efficacy of these therapies and overcome resistance. Future research should focus on targeting EGFR trafficking, autophagy, and metabolism to enhance the effectiveness of EGFR inhibitors in cancer treatment.The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that plays a critical role in epithelial cell physiology. In cancer, EGFR is a driver of tumorigenesis, often amplified or mutated. Its activation can lead to uncontrolled cell proliferation and resistance to therapy. While the canonical EGFR signaling pathway is well understood, recent studies have revealed noncanonical functions of EGFR in stress-induced trafficking, autophagy, and energy metabolism. These functions are increasingly recognized as important in cancer progression and resistance. EGFR signaling is regulated by endocytosis, which influences its trafficking and signaling outcomes. The EGFR can undergo clathrin-mediated endocytosis (CME) and nonclathrin endocytosis (NCE), with NCE being more active at higher EGF concentrations. EGFR trafficking is also influenced by cellular stress, such as UV radiation, hypoxia, and oxidative stress, which can trigger ligand-independent EGFR internalization and signaling. These stress-induced pathways can promote cancer cell survival and resistance to therapy. EGFR also plays a role in autophagy, which is critical for cellular homeostasis. In nutrient-rich conditions, EGFR inhibits autophagy by phosphorylating Beclin-1, while in serum-starved conditions, it promotes autophagy. EGFR can also localize to the nucleus and mitochondria, where it influences cell survival, metabolism, and resistance to apoptosis. EGFR signaling is involved in metabolic reprogramming, including aerobic glycolysis and fatty acid synthesis, which support cancer cell proliferation. EGFR-targeted therapies, such as monoclonal antibodies and small-molecule inhibitors, are used in cancer treatment. However, resistance often develops due to EGFR mutations, alterations in other kinases, or feedback loops that counteract EGFR inhibition. Understanding the role of membrane trafficking in EGFR signaling could improve the efficacy of these therapies and overcome resistance. Future research should focus on targeting EGFR trafficking, autophagy, and metabolism to enhance the effectiveness of EGFR inhibitors in cancer treatment.