Two classes of anti-EGF receptor (EGFR) agents, monoclonal anti-EGFR antibodies and small-molecule EGFR tyrosine kinase inhibitors, have been used for the treatment of non-small-cell lung cancer (NSCLC). However, only a subset of patients will benefit from EGFR-targeted therapy. The discovery of biomarkers that select the appropriate patients for the therapy and predict the responses to the therapy is urgently needed. Molecular genetic analyses provide new insights into EGFR pathway alterations and demonstrate promise for predicting the clinical outcome of patients with NSCLC. In this article, we summarize the latest available knowledge on the clinical impact of EGFR mutations, gene copy number, EGFR overexpression, phosphorylation expression and the alteration of the EGFR pathway downstream factors in predicting the response to EGFR-targeted therapy in NSCLC patients. The role of KRAS and BRAF mutations and ALK rearrangement in lung cancer-targeted therapy, are also reviewed.