Lung cancer is the second most common cancer and the leading cause of cancer-related deaths in the United States. Moreover, advanced non-small-cell lung cancer (NSCLC) is considered an incurable disease and current treatment approaches provide marginal improvement in overall survival at the expense of substantial morbidity and mortality, highlighting the need for new, less toxic treatment approaches. Tyrosine kinase inhibitors, such as erlotinib (Tarceva®), have been developed and approved as maintenance, second- and third-line treatment options in unselected advanced NSCLC patients (2, 15). However, subgroup analyses from the initial clinical trials consistently showed that patients with epidermal growth factor receptor (EGFR) mutations who received erlotinib had higher rates of response and better progression-free and overall survival, leading to clinical trials specifically focused on the use of tyrosine kinase inhibitors as first-line therapy in these patients. We examined the published literature on the analytic validity, clinical validity, and clinical utility of EGFR mutational testing in guiding first-line therapy use of erlotinib to treat advanced NSCLC and we briefly summarized the current lung cancer screening guidelines. The primary goal was to provide a basic overview of EGFR mutational testing and use of erlotinib as first-line therapy and identify gaps in knowledge and evidence that affect the recommendation and adoption of the test in advanced NSCLC treatment management strategies.