Abstract: Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer. Small molecular drug therapy that targets epidermal growth factor receptor (EGFR) has significantly improved the survival and quality of life of patients with advanced NSCLC. However, almost all of these patients experience drug resistance. Despite research advances, some of the molecular mechanisms underlying acquired remain unknown. This review focuses on recent studies on EGFR mutations, clinical trials of EGFR-targeted drugs, and research on the mechanisms and therapies of acquired resistance. Several molecular testings are needed to clarify the mechanism underlying acquired resistance to achieve personalized care of these patients.