HER2 mutations, largely exon 20 in-frame insertions, have been described as an oncogenic driver alteration in 1% to 4% of NSCLC, exclusively in adenocarcinoma histology. The prognostic implication of these alterations is not known. Phase I and II trial data suggest that afatinib, neratinib and dacomitinib have some activity in this molecular subgroup. No comparative data, or any data regarding the activity of pertuzumab or trastuzumab-emtansine is available. HER2 deregulation either by protein overexpression or gene amplification, has little clinical relevance to date, as trials investigating trastuzumab activity merely suggest a benefit in the very small minority of patients whose tumor highly overexpresses HER2, a subpopulation that amounts to 2% to 6% of mostly adenocarcinomas.