Lung cancer is the leading cause of cancer deaths worldwide. Non-small-cell lung cancer (NSCLC) is the largest subgroup of the disease and accounts for approximately 80% of lung cancers. Most patients with NSCLC are diagnosed with locally advanced or metastatic disease. The current treatment options for such patients are associated with substantial limitations in efficacy and safety. Targeted therapies have provided some improvement in clinical outcomes. Recent efforts have focused on identifying specific markers that are predictive of response to treatment. A pretreatment detection of such markers could facilitate a more personalized and specific approach to therapy, whereby the most appropriate and efficacious treatment is selected for a specific subset of patients. Such a tailored approach would maximize both the therapeutic index and cost-effectiveness of treatments. In addition, several novel agents are under development, which may have the potential for overcoming acquired resistance to existing treatments. This supplement will review the current and emerging treatments for patients with advanced NSCLC and the molecular predictors of response that may facilitate the future clinical application of personalized medicine.