Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been first-line therapy in the treatment of non-small cell lung cancer (NSCLC) harboring sensitive mutations. Progression inevitably happens after 10-14 months of first- or second-generation EGFR TKIs treatment for acquired resistance. Owing to the successful identification of T790M, third-generation EGFR TKIs such as osimertinib were developed to target such resistance mutation. Nowadays, osimertinib has shown its efficacy both in first-line and second-line after resistance to previous generations of TKI treatment of -mutant NSCLC. However, drug resistance also emerges on third-generation EGFR TKIs. Multiple mechanisms of acquired resistance have been identified, and some novel strategies were reported to overcome third-generation TKI resistance. Immune checkpoint inhibitors (ICIs) have dramatically changed the prognosis of selected patients. For patients with -addicted metastatic NSCLC, ICIs have also revealed a potential role. In this review, we will take stock of mechanisms of acquired resistance to third-generation TKIs and discuss current challenges and future perspectives in clinical practice.