Gefitinib, an epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI), has been approved in Japan for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) based on Phase II clinical trials since 2002. Erlotinib, another EGFR-TKI, was also approved a few years thereafter. In 2004, activating mutations in the EGFR gene were discovered to be a predictive biomarker for EGFR-TKI treatment, and gefitinib, which is not effective for patients with EGFR wild-type NSCLC, has since been used only in patients with EGFR-mutated NSCLC. In contrast, erlotinib is potentially effective for the treatment of EGFR wild-type NSCLC. Similar to gefitinib, erlotinib is also effective for EGFR-mutated NSCLC and has been used as an initial treatment for patients with advanced EGFR-mutated NSCLC. Both gefitinib and erlotinib can be used in a Japanese clinical setting. The approved daily dose of erlotinib (150 mg) is equal to the maximum tolerated dose of erlotinib. In contrast, the daily dose of gefitinib has been set at 250 mg, which is approximately one-third of the maximum tolerated dose of gefitinib. Accordingly, a higher serum concentration can be achieved using erlotinib, compared with gefitinib. This advantage can be applied to the treatment of central nervous system metastases (brain metastasis and carcinomatous meningitis), the treatment of which is complicated by the difficulty drugs have penetrating the blood–brain barrier. Although patients with EGFR-mutated NSCLC respond dramatically to EGFR-TKIs, some patients have a poor response and the majority eventually undergo disease progression. To overcome such resistance, several novel treatment strategies, such as combination therapy and next-generation EGFR-TKIs, have been attempted.