Acquired resistance to tyrosine kinase inhibitors (TKIs) represents the Achilles' heel of targeted treatment in lung cancer. Epidermal growth factor receptor (EGFR)-TKIs are considered the standard first-line treatment for patients with EGFR mutant non–small cell lung cancer; however, after a median of 9 to 12 months, virtually all patients develop acquired resistance, which is mediated by the development of an EGFR-T790M secondary mutation in approximately 60% of cases. Different mechanisms of acquired resistance have also been described with lower incidence, including mutations in other driver oncogenes or phenotypic transformation. Herein, we report the first case of a patient with EGFR-mutant lung adenocarcinoma with a long-lasting response to first-line erlotinib treatment who acquired resistance to treatment because of acquisition of both EGFR-T790M mutation and “high-grade” large cell neuroendocrine transformation. This case also shows how resistance to third-generation EGFR-TKI osimertinib can be mediated by the development of phenotypic neuroendocrine transformation, which in the present case occurred during first-line treatment with erlotinib. In addition, our report highlights the pivotal role of rebiopsy and of molecular profiling at the time of progression to guide clinicians to choose the right therapy for the right patient.