TOne of the most important pathways in non-small cell lung cancer (NSCLC) is the epidermal growth factor receptor (EGFR) pathway.This pathway aff ects several crucial processes in tumor development and progression, including tumor cell proliferation, apoptosisregulation, angiogenesis, and metastatic invasion. Targeting EGFR is currently being intensely explored. We are witnessing thedevelopment of a number of potential molecular-inhibiting treatments for application in clinical oncology. In the last decade, thetyrosine kinase (TK) domain of the EGFR was identifi ed in NSCLC patients, and it has responded very well with a dramatic clinicalimprovement to TK inhibitors such are gefi tinib and erlotinib. Unfortunately, there were primary and/or secondary resistance to thesetreatments, as shown by clinical trials. Subsequent molecular biology studies provided some explanations for the drug resistancephenomenon. The molecular mechanisms of resistance need to be clarified. An in-depth understanding of these targeted-therapyresistance may help us explore new strategies for overcoming or reversing the resistance to these inhibitors for the future of NSCLC treatment.