 Despite being effective in treating non-small cell lung cancer driven by epidermal growth factor receptor mutations, patients eventually develop resistance to EGFR tyrosine kinase inhibitors due to various mechanisms such as secondary mutation, T790M, activation of alternative pathways, C-MET, HGF, AXL, aberrance of downstream pathways, KRAS mutations, loss of PTEN, impairment of EGFR-TK as mediated apoptosis pathway, BCL2 like 11-slash-BIM deletion polymorphism, histologic transformation, ATP, binding cassette, ABC, transporter effusion, etc. Potential targets for new therapeutic strategies include these resistant mechanisms. This article was authored by Lihua Huang and Li Wufu.