Oncogenic mutations and amplifications in the erythroblastic oncogene B (), or human epidermal growth factor receptor 2 (), have emerged as distinct oncogenic drivers and drug targets in non-small cell lung cancer (NSCLC). Each genomic alteration occurs in 2-4% of NSCLC by next generation sequencing and is associated with constitutive HER2 activation. The most common mutations in NSCLC are exon 20 mutation A775_G776insYVMA mutation in the kinase domain and S310F mutation in the extracellular domain. Unlike in breast and gastric cancer, HER2 protein overexpression in NSCLC is not validated to be a biomarker predictive of clinical response to HER2-targeted agents. High HER2 protein overexpression by immunohistochemistry (3) only occurs in 2-4% of NSCLC. Until now HER2-targeted agents (such as afatinib and ado-trastuzumab emtansine) only demonstrate modest clinical activity in patients with -mutant NSCLC. Retrospective studies show concern for inferior clinical benefit of immune checkpoint inhibitors in -mutated NSCLC. Therefore, platinum-based chemotherapy with or without an anti-angiogenesis inhibitor remains the first line standard treatment for this patient population. In May 2020 trastuzumab deruxtecan (T-DXd) received the U.S. Food and Drug Administration breakthrough therapy designation for -mutant metastatic NSCLC, and was added as an option for -mutant NSCLC to the NCCN guidelines V1.2021. A global phase III study of pyrotinib compared to docetaxel as a second line therapy for advanced NSCLC harboring exon 20 mutations was just opened for enrollment in September 2020. In this review, we highlight the current knowledge and perspectives on targeting- genomic alterations in NSCLC.