Lung cancer with epidermal growth factor receptor (EGFR) activating mutations, such as exon 19 deletion and exon 21 L858R point mutation, responds to the EGFR-tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib. Recent clinical trials demonstrated much longer progression-free survival for EGFR mutant lung cancer patients when treated with gefitinib and erlotinib compared with conventional chemotherapy. Therefore, EGFR-TKIs are recommended as first-line therapy for EGFR mutant lung cancer patients by lung cancer practice guideline in the Japan Lung Cancer Society and in National Comprehensive Cancer Network. However, almost without exception, the responders relapse after various times due to acquiring resistance to EGFR-TKIs. Recently, several mechanisms were reported to induce acquired resistance to reversible EGFR-TKIs for lung cancer with EGFR-activating mutations. Of these, the secondary T790M mutation in EGFR is the most investigated cause of acquired resistance to the reversible EGFR-TKIs. Irreversible EGFR-TKIs were expected to overcome the reversible EGFR-TKI resistance of lung cancer caused by T790M mutation in EGFR. On the other hands, the novel resistant mechanisms, such as MET amplification and HGF overexpression, are also found. We have shown that the combined therapy of MET inhibitor and EGFR-TKI overcome caused by these mechanisms. More recently, mutant EGFR selective EGFR-TKIs, which are active to mutant EGFR with exon 19 deletion, L858R, and T790M but not wild-type EGFR, have been developed. In this symposium, we will overview the molecular mechanisms of EGFR-TKI resistance and discuss novel therapeutic strategies that are under development for overcoming the resistance in lung cancer.