Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer death in the developed world. Platinum-based chemotherapy is the therapeutic foundation of treatment both in the metastatic and adjuvant setting and targeted therapies are entering standard treatment paradigms. However, many patients do not obtain benefit from cytotoxic agents or newer targeted therapies, but are still exposed to their toxic effects. Reliable biomarkers to select treatments for patients most likely to obtain benefit have, therefore, been an important focus for many research groups. In this paper, we review current predictive and prognostic biomarkers in NSCLC. We assess their potential clinical use and explore recent data pertaining to genome-wide approaches for treatment selection in NSCLC.