Abstract: Targeted therapy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) has been the standard modality as the first-line treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC). The first- and second-generation EGFR-TKIs have shown significant efficacy in NSCLC patients with EGFR-sensitive mutations and EGFR T790M mutation is the main resistance mechanism of the first- and second-generation EGFR-TKIs. The third-generation EGFR-TKIs, represented by osimertinib, has been approved to overcome the EGFR T790M mutation in patients who are resistant to the first- or second-generation TKIs, which brings more survival benefits for patients with advanced NSCLC. However, the development of acquired drug resistance is inevitable. In this review, we summarize the research progress in resistance mechanisms of advanced NSCLC to the third-generation EGFR-TKIs and the potential overcoming strategies.