Gefitinib, also known as ERSA, as a representative of EGFR-TKI is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) that has received prior chemotherapy or is not amenable to chemotherapy. It has a good clinical outcome. It is often used for second- and third-line treatment of lung cancer. However what should we do if gefitinib treatment fails? How to treat patients who have failed gefitinib treatment is a global concern. Firstly, different mechanisms of treatment failure, such as drug resistance gene T790M, c-met signaling pathway, insulin growth factor receptor (IGFR-1) gene, can be used according to the corresponding inhibitors, which is a hot spot of international research at present. Secondly, anti-angiogenic therapy can be considered, such as sorafenib and sunitinib. Also, whether chemotherapy can be reactivated our study found that both mutant and wild-type cells exist in lung cancer, and after inhibiting mutant cells with EGFR-TKI, wild-type cells become the dominant cells, which leaves room for re-chemotherapy. Clinical trials related to these aspects are underway. It has been proposed that the resistance may be reversed with the extracellular monoclonal antibody cetuximab. The possible mechanism is that the EGFR extracellular structural domain is altered so that the TKI cannot bind to it, and the monoclonal antibody can open the structural domain so that the TKI can re-bind to it. In addition, some people have proposed the EGFR “holidayperiod” hypothesis, which suggests that chemotherapy and TKI can be used sequentially, and those with progressive disease after chemotherapy can be switched to TKI, and those with TKI failure can be reintroduced to the original chemotherapy regimen, and some patients will still be effective. There are also clinical trials underway.