While it took about 45 years from the discovery of EGFR to the clinical appraisal of the first anti‐EGFR antibodies in CRC treatment, < 15 years were necessary to intercept intrinsic and acquired mechanisms of resistance, develop integrated strategies to tackle other oncogenic nodes along the pathway, and tailor rechallenge strategies based on the circulating levels of mutations responsible for resistance. This evidence concerns the gene EGFR and colorectal carcinoma.