Abstract: The incidence of lung cancer ranks the first among malignancies in China. Studies on molecular-targeted therapy with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have atracted more attention. However, many patients with non-small cell lung cancer (NSCLC) manifest primary symptoms at the beginning of therapy; other patients develop drug resistance after they receive EGFR-TKI treatment for a period. This review describes the progress on drug resistance mechanisms of EGFR-TKIs at a molecular level and the significance of such inhibitors in clinical application.