Abstract: At present, the morbidity and mortality of lung cancer still rank first among all kinds of cancers in the world. Lung cancer diagnosis is often in the intermediate and terminal stage, and its radiotherapy and chemotherapy are not effective, with high postoperative recurrence and metastasis rate. Targeted therapies, such as epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), have significantly improved clinical outcomes of patients with advanced non-small cell lung cancer (NSCLC) complicated with EGFR mutation. However, the prognosis is still poor due to the occurrence of drug resistance. This article reviews the research progress of TKIs resistance mechanism in NSCLC patients with EGFR mutation, so as to provide reference for clinical exploration of new treatment strategies.