The article reviews the quest to overcome resistance to epidermal growth factor receptor (EGFR)-targeted therapies in lung, colorectal, pancreatic, and head and neck cancers. It highlights the increasing complexity of resistance mechanisms, which include mutations such as T790M in EGFR, oncogenic shifts like MET amplification or HER2 upregulation, and impairments of pathways essential for apoptosis. The authors discuss the development of criteria to assess the clinical relevance of resistance mechanisms and strategies to overcome resistance, including the use of irreversible EGFR inhibitors, combination therapies, and targeting downstream pathways. They emphasize the importance of understanding tumor heterogeneity and the evolution of drug resistance, and suggest that adaptive clinical trial designs and monitoring of circulating tumor DNA may be promising approaches. The article concludes by emphasizing the need for perseverance, creativity, and collaboration in cancer research to overcome resistance and improve patient outcomes.The article reviews the quest to overcome resistance to epidermal growth factor receptor (EGFR)-targeted therapies in lung, colorectal, pancreatic, and head and neck cancers. It highlights the increasing complexity of resistance mechanisms, which include mutations such as T790M in EGFR, oncogenic shifts like MET amplification or HER2 upregulation, and impairments of pathways essential for apoptosis. The authors discuss the development of criteria to assess the clinical relevance of resistance mechanisms and strategies to overcome resistance, including the use of irreversible EGFR inhibitors, combination therapies, and targeting downstream pathways. They emphasize the importance of understanding tumor heterogeneity and the evolution of drug resistance, and suggest that adaptive clinical trial designs and monitoring of circulating tumor DNA may be promising approaches. The article concludes by emphasizing the need for perseverance, creativity, and collaboration in cancer research to overcome resistance and improve patient outcomes.