Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) are effective in some patients with advanced non-small cell lung cancer (NSCLC), whether as first-line or second- or third-line therapy, with significant benefits especially in women, nonsmokers, adenocarcinoma patients, and Asian populations.Three questions need to be asked first about the use of EGFR-TKI agents for the treatment of clinically advanced NSCLC Clarity: What to use? Who uses the drug? When to use it? Erlotinib has the following advantages over gefitinib. What to use? First, different dose designs of EGFR-TKI agents result in different blood concentrations, with erlotinib blood trough concentrations being about 9 times higher than gefitinib at the recommended dose. Second, erlotinib may be more effective than gefitinib in EGFR wild-type tumors. In EGFR wild-type NSCLC, second-line erlotinib was comparable to chemotherapy in terms of overall survival (0S), with erlotinib showing a trend toward benefit; in contrast, in patients with EGFR wild-type NSCLC, there was no trend toward benefit with gefitinib compared with placebo. Again, erlotinib had better control of central nervous system (CNS) metastases and is a reasonable treatment option for those who develop brain and soft meningeal metastases after effective initial gefitinib treatment. A retrospective analysis of 1122 patients with advanced NSCLC who received erlotinib or gefitinib at 5 centers showed that the median OS (10.7 months versus 9.6 months, P=0.013) and median progression-free survival (PFS, 4.6 months versus 3.6 months, P=0.027) were significantly better in the erlotinib group than in the gefitinib group; the favorable efficacy of erlotinib was demonstrated in major clinical subgroups, including adenocarcinoma patients who did not smoke or had smoked lightly and male, smoking, non-adenocarcinoma patients (the poor prognosis subgroup). Who uses the drug? EGFR mutations are a major consideration in the selection of patients to be treated. For patients with unknown EGFR status, erlotinib may be considered. For EGFR activating mutations, erlotinib should be selected for those with CNS metastases and for those without CNS metastases, either erlotinib or gefitinib. for EGFR wild-type patients, treatment with erlotinib is generally indicated. If the specimen is ineligible or the EGFR status is unknown, erlotinib is considered as a treatment option. When to use? Erlotinib can be used as first-line treatment for patients with an associated EGFR activating mutation, with a median PFS of up to 13.1 months in chemotherapy-naïve patients with advanced NSCLC who are on erlotinib. The efficacy of erlotinib for second-line treatment has also been demonstrated in studies. Chinese patients with advanced NSCLC treated with erlotinib (first- or second-line) had higher control rates and longer PFS and OS compared to gefitinib. As for the choice of drugs, the main EGFR-TKI agent-targeted drugs currently available for advanced non-small cell lung cancer (NSCLC) treatment are erlotinib, gefitinib and erlotinib.