Lung cancer is one of the most common cancers worldwide. Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. Chemotherapy for patients with advanced NSCLC has only marginally improved overall survival; whereas recently developed small-molecule compound epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) demonstrate strong efficacy in treating advanced NSCLC. However, only a part of patients with NSCLC is sensitive to the treatment of EGFR TKIs if they have certain mutations of EGFR gene in their tumors. Patients without EGFR mutations show innate resistance to EGFR TKIs. Furthermore, approximately 20%-30% of patients with EGFR mutations also do not response to EGFR TKIs. In this review, the mechanisms underlying the primary resistance to EGFR TKIs in advanced NSCLC, especially in those with EGFR sensitive mutations, are summarized.