In non-small-cell lung cancer (NSCLC), the identification of oncogenic driver mutations led to the definition of different clinical entities with different therapeutic opportunities, as demonstrated in patients harboring EGF receptor (EGFR) mutations or anaplastic lymphoma kinase translocations. Human EGFR2 (or HER2) has an established role as a prognostic and predictive factor in breast cancer. Although HER2 deregulation, including overexpression, amplification and mutation, has been described in NSCLC, its role as a therapy biomarker remains undefined. In the last few years, there has been a growing interest on HER2 mutation, with few anecdotal or retrospective studies suggesting a relevant role for this biomarker. This review discusses the prognostic and predictive impact of HER2 deregulation and the clinical implications of anti-HER2 strategies in NSCLC.