Lung cancer ranks the first in the mortality rate among all cancers, and non-small cell lung carcinoma (NSCLC) accounts for about 80% of the incidence of lung cancer. In recent years, the drugs targeting specific molecules have been developed rapidly. The epidermal growth factor receptor-tyrosine kinase inhibitors (EGFRTKIs) have achieved good results in the treatment of patients with NSCLC. Currently, there are three generations of EGFR-TKIs, and the treatment outcome of these drugs surpasses traditional chemotherapies. However, the problems of acquired resistance remains in the course of treatment. In this review, research progress of the mechanisms of acquired resistance is divided into two parts:EGFR-dependent pathway and EGFR-independent pathway. The EGFR-dependent pathway mainly includes EGFR gene mutations, whereas the EGFR-independent pathways include HER2 amplification, BIM deletion, activation of HGF/c-Met pathway, activation of IGF1R, RAS mutation, PTEN deletion, epithelial-mesenchymal transition, PUMA loss, and high levels of expression of VEGF or IL-6. These interconnected mechanisms are linked with acquired resistance to EGFR-TKIs in NSCLC.