Abstract: Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancer. There is a great many NSCLC patients have been in advanced stage when diagnosed. As a result, people pay more attention to curing advanced NSCLC. The standard treatment to advanced NSCLC is platinum-based combined chemotherapy. Then exploring new therapies is extremely urgent to us. With the development of medical molecular biology techniques and the study of molecular pathogenesis of lung cancer, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib are becoming promising therapies for parts of patients with NSCLC. The compounds which target the EGFR play an important role in the treatment of the NSCLC. However, after a period of treatment (median time is 6 to 12 months), most patients will develop drug resistance to EGFR-TKIs. Intense research in these NSCLCs has identified two major mechanisms of resistance to TKIs: Primary and acquired resistances. The aim of this article was to summarize the development of the resistance mechanisms and new overcoming strategies on better treatment of drug resistant cancer cells in EGFR-mutant NSCLC.