Even with the introduction of targeted agents and the establishment of multiple lines of therapy, the median survival for patients with advanced non-small cell lung cancer (NSCLC) does not considerably extend beyond 1 year. Emerging research suggests that clinical characteristics alone are insufficient for selecting patients for therapies that may confer significant survival benefit. The discovery of predictive and prognostic molecular markers such as gene mutations in EGFR and KRAS as well as high tumor expression levels of DNA repair pathway components ribonucleotide reductase subunit 1 and excision repair cross-complementing group 1 has sparked an interest in the development of individualized therapy as a strategy for increasing survival in patients with NSCLC. Techniques to analyze molecular biomarkers, such as immunohistochemistry, fluorescence in situ hybridization, polymerase chain reaction, and, more recently, gene microarray techniques, are being investigated for their potential to accurately predict an individual patient's response to therapy. Many prospective trials are still needed to clarify and confirm the utility of molecular biomarkers for guiding treatment selection, and continued participation in clinical trials is critical for the development of tools to provide customized treatment plans for patients with NSCLC.