Epidermal growth factor receptor (EGFR) is a critical target in the treatment of nonsmall cell lung cancer (NSCLC). The mutations involving EGFR are more prevalent in patients of Asian ancestry, women, never smokers, and those with adenocarcinoma histology. Primary mechanism of resistance to EGFR-TKIs includes in frame insertion mutation in exon 20, de novo T790M mutation also on exon 20, activating mutations in KRAS, loss of PTEN, and amplification of c-MET whereas acquired resistance results from development of secondary alteration in ATP domain of T790M. There are many novel targeting agents in development to overcome resistance to EGFR TKIs.