Therapeutic strategies targeting the epidermal growth factor receptor (EGFR) are being evaluated in a number of ongoing clinical studies in non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are currently used worldwide to treat advanced refractory NSCLC, whereas the efficacy of anti-EGFR monoclonal antibodies remains to be established. Using molecular profiling to select patients to receive earlier EGFR targeted therapy as first-line treatment or in the adjuvant setting is an area of active research. Based on preclinical data, combining EGFR TKIs with other treatment modalities has promise, and clinical validation is underway. A new generation of irreversibly bound EGFR TKIs is being developed, and insights into the molecular biology of NSCLC should help to better define the patients who are most likely to benefit from these compounds. We summarize updates on EGFR targeted therapies that were presented during the sixth annual Targeted Therapies for the Treatment of Lung Cancer Conference in Los Angeles, CA; January 27-28, 2006.