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Rapidly developing molecular biology techniques have been employed to identify cancer driver genes in specimens from patients with non-small cell lung cancer (NSCLC). Inhibitors and antibodies that specifically target driver gene-mediated signaling pathways to suppress tumor growth and progression are expected to extend the survival time and further improve the quality of life of patients. However, the health of patients with advanced and metastatic NSCLC presents significant challenges due to treatment resistance, mediated by cancer driver gene alteration, epigenetic alteration, and tumor heterogeneity. In this review, we discuss two different resistance mechanisms in NSCLC targeted therapies, namely changes in the targeted oncogenes (on-target resistance) and changes in other related signaling pathways (off-target resistance) in tumor cells. We highlight the conventional mechanisms of drug resistance …