The epidermal growth factor receptor (EGFR) is a cellular transmembrane receptor with tyrosine kinase enzymatic activity which plays a key role in human cancer. EGFR-dependent signaling is involved in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Targeting the EGFR has played a central role in advancing non small cell lung cancer (NSCLC) research, treatment and patients outcome over the last several years. Two types of anti-EGFR targeting agents have reached advanced clinical development: monoclonal antibodies (Mabs) and small molecule inhibitors of the EGFR tyrosine kinase enzymatic activity (TKIs). Among TKIs gefitinib and erlotinib has been approved for the treatment of advanced NSCLC. Some clinical features such as never-smoking, female gender, East Asian origin, adenocarcinoma histology, and some biological characteristics such as somatic EGFR gene mutations and increased EGFR gene copy number, are associated with a greater benefit from treatment with TKIs. This review focuses on the clinical evidence on the anticancer activity of EGFR-TKIs in the treatmnent of NSCLC patients.