This review discussed EGFR-TKI resistance mechanisms and its clinical implications in NSCLC, summarized current EGFR-TKI-based combination therapy regimens and overviewed novel treatment approaches including nanoparticles encapsulating non-coding RNAs for overcoming EGFR-TKI resistance in NSCLC. The gene discussed is EGFR; the disease is non-small cell lung carcinoma.