Discovery of activating mutations of the EGFR gene in adenocarcinoma of the lung in 2004 opened the door to a new era for personalized therapy in thoracic oncology. Lung cancers with EGFR mutation are highly sensitive to EGFR-tyrosine kinase inhibitors (TKI) such as gefitinib, erlotinib, or afatinib, resulting in significantly prolonged progression free survival compared with those treated with platinum doublet chemotherapy. However, acquired resistance inevitably develops usually after a median of 10∼12 months. The mechanisms for this resistance have been extensively studied and can be classified into 1) target gene alteration, 2) activation of bypass / accessory pathway, and 3) histologic transformation (Fig). The most common (50∼60%) mechanism for acquired resistance to the EGFR-TKI is a missense mutation at codon 790 of the EGFR gene resulting in substitution of threonine to methionine (T790M). This amino acid change reduces affinity between EGFR kinase and EGFR-TKI compared with that between EGFR-kinase and ATP, leading to reactivation of down-stream pathways. L747S, D761Y, and T854A are also known as secondary mutations that cause acquired resistance, but they are very rare. In these cases, cancer cells are still addicted to or dependent on EGFR pathway. Amplification of the MET gene which codes for a receptor of hepatocyte growth factor (HGF) was the first that was identified as a bypass track resistance mechanism against EGFR-TKI. Following this report, aberrant activation of other receptor tyrosine kinases such as HER2, HER3, AXL, IGF1R, have been reported. It is also shown that some ligands for the receptor tyrosine kinases such as HGF, FGF or IGF cause acquired resistance to EGFR-TKIs. Similarly, alteration of downstream molecule cause resistance. These molecules include BRAF, PTEN, JAK2, CRKL, DAPK, NF-kB, or PUMA. The third mechanism of acquired resistance is histologic transformation that includes small cell lung cancer transformation and epithelial-mesenchymal transition EMT). Exact mechanisms of these histologic changes are not fully understood. However, AXL, Notch-1, TGFb pathway activation as well as down regulation of MED12 ((Mediator Complex Subunit 12) have been proposed as mechanisms of EMT. Then, How are we able to cope with these resistance? For T790M gatekeeper mutations, the third generation EGFR inhibitors that selectively inhibit EGFR-T790M while sparing the wild-type EGFR are active. One of these drugs, osimertinib is already approved and gives a response rate of ∼60% and progression free survival of ∼11 months. Therefore, identification of T790M at the time of disease progression by rebiopsy is important. We have recently found that three other secondary EGFR mutations implicated in acquired resistance are also sensitive to osimertinib. Tumor resistance caused by activation of accessory pathways can be theoretically coped with by combination of the inhibitor of EGFR and involved molecules. However, because of rarity of each mechanism, there is no clear evidence whether these combination therapies will actually improve patient outcome In other cases, cytotoxic chemotherapy is still an important strategy. According to the IMPRESS study, median progression free survival for patients without T790M who received cisplatin plus pemetrexed was 5.4 months. Even with these strategies, cancer cells are smart enough to escape from the therapy using other mechanisms. Heterogeneities in terms of resistant mechanisms within a single patient become evident when specific therapeutic pressure persists. Therefore, we also need to have armamentarium that utilizes other mechanisms to cure lung cancer. Recent advances of immunotherapy targeting immune checkpoints appear attractive in this respect. These mechanism-driven therapeutic approaches will convert this fatal disease into a more chronic disorder, and eventually into a curable disease with the least patient burden. Adenocarcinoma, EGFR, Resistance, T790M