The development of EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) has shifted our treatment paradigm in non-small-cell lung cancer (NSCLC). Erlotinib is an orally administered, first-generation, reversible EGFR TKI. The activating mutations in the tyrosine kinase domain of EGFR are considered to be the most important biomarkers to predict responses to erlotinib because these mutations are the oncologic drivers of some NSCLC by stimulating downstream signaling, such as the RAS–RAF–MEK–ERK, PI3K–AKT and STAT pathways. In the USA, erlotinib is the preferred front-line therapy in advanced EGFR-mutated NSCLC, with superior response rates and progression-free survival (PFS) in comparison to standard chemotherapy. On the other hand, the majority of patients with NSCLC do not harbor EGFR mutations and are considered as EGFR wild-type, although EGFR signaling may still be activated through protein overexpression or increased gene copy numbers. Indeed, erlotinib is currently approved for the treatment of unselected chemorefractory advanced lung cancer patients, as well as maintenance therapy after first-line chemotherapy. Its activity is clinically relevant, but usually modest in NSCLC with EGFR wild-type. Thus, when and in which setting could we consider erlotinib in the treatment of EGFR wild-type lung cancer?