Given the successful identification of epidermal growth factor receptor EGFR T790M, the third generation EGFR tyrosine kinase inhibitor (TKI), osimertinib (OSI, AZD9291), was developed to target EGFR T790M mutation. OSI was approved for the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR T790M mutation. However, the disease would progress after the patient received OSI treatment for approximately 10 months. Resistance mechanisms to OSI, such as additional mutation of EGFR and alternative kinase activation, were recently identified, and some novel therapeutic strategies were proposed to overcome OSI resistance. In this review, the resistance mechanisms and therapeutic strategies for OSI-resistant NSCLC were summarized to direct further use of OSI and aid in the development of novel drugs or strategies for OSI-resistant NSCLC. (C) 2018 Elsevier B.V. All rights reserved.