EGF receptors (EGFRs) are often overexpressed or constitutively activated in non-small-cell lung cancer, and are an important therapeutic target. EGFR signaling can be blocked with tyrosine kinase inhibitors (TKIs) and anti-EGFR antibodies. Three EGFR-TKIs are approved as initial monotherapies in patients with EGFR-activating mutations, and erlotinib has a role as maintenance and second-line therapy. Investigational anti-EGFR monoclonal antibodies plus standard first-line therapy improve survival in patients with advanced non-small-cell lung cancer, especially in tumors with high EGFR expression. Anti-EGFR antibodies inhibit EGFR signaling and have the potential to stimulate antibody-dependent cell-mediated cytotoxicity. Multikinase TKIs are investigational as first- and second-line therapies, as monotherapies and in combination with chemotherapy. This article summarizes the available clinical data for EGFR-targeted therapies.