T790M mutation is the most common mechanism of resistance to first- and second-generation tyrosine kinase inhibitors (TKI) for epidermal growth factor receptor (EGFR). Several third-generation EGFR mutant-selective TKIs are being explored to conquer this resistance. AZD9291 (osimertinib, TAGRISSO) has been approved for treatment of the metastatic EGFR T790M mutation-positive non-small cell lung cancer. Unfortunately, these lung cancer patients eventually developed resistance to these drugs after ten months. A better understanding of the mechanisms of resistance to these third-generation EGFR inhibitors is critical for developing new strategies to treat these patients. EGFR Cys797Ser(C797S) mutation, located within the tyrosine kinase domain, was recently reported to be a potential mechanism of resistance to irreversible EGFR inhibitors such as AZD9291, HM61713, WZ4002, and CO-1686 in T790M-positive patients (refer to the figure below). Therefore, the novel selective (4th generation) inhibitor overcoming the C797S mutant should be developed.