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Targeted therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) is regarded as the main accepted first-line treatment on EGFR mutation in non-small cell lung cancer (NSCLC). Although targeted therapy for the first and two generation of TKIs may lead to longer progression-free survival (PFS) and better tolerance for patients, the long-term treatment will inevitably lead to drug resistance. Among them, more than 50% of acquired resistance is associated with T790M mutation. The latest guidelines from the National Comprehensive Cancer Network (NCCN) have been proposed that the three generation of TKI (Osimertinib) can be used in first-line TKI therapy progress with detecting T790M mutations in patients. Encouraged by the treatment time of the median PFS up to 13 months and sequential EGFR-TKIs treatment which brought from the three generation of TKI, we also face serious challenges, such as how to achieve the detecting and the dynamic monitoring of T790M, the research progress, mechanism of drug resistance and subsequent treatment of the existing three generation TKI etc. This article will revolve around the above hot issues.