The therapeutic strategy of non-small cell lung cancer (NSCLC) is dramatically changed with the introduction of molecular targeted drugs in the last years, resulting in a series of results in histologic and molecular level. The discovery of epidermal growth factor receptor (EGFR) mutation, Kirsten rat sarcoma (KRAS) viral oncogene mutation and anaplastic lymphoma kinase (ALK) rearrangement, has profoundly influenced the development of treatment of NSCLC. Recently, there is a renewed interest in the human epidermal growth receptor 2 (HER2), where genetic alteration in NSCLC is associated with the different sensetivity of EGFR tyrosine kinase inhibitors (TKIs), to have a prognostic effect. HER2 amplification in EGFR mutation tumors may become a mechanism of acquired resistance to the TKIs. Besides, HER2 mutation may become a novel therapeutic strategy of NSCLC.