Lung cancer is the leading cause of cancer-related mortality in the United States with 222,520 new cases and 157,300 deaths anticipated in 2010. The primary objective of any cancer treatment is to improve patient outcomes including overall survival and quality of life while minimizing treatment toxicity. As our knowledge of the molecular mechanisms involved in the pathogenesis of lung cancer evolves, improved methods of therapeutic selection may help clinicians better realize these goals. Such selection may be accomplished by examining biomarkers within patients' tumors that may provide prognostic information such as risk of recurrence in early stage disease or predict benefit from specific therapies regardless of disease stage. Three such biomarkers have emerged--excision repair cross-complementation group 1, the regulatory subunit of the ribonucleotide reductase enzyme, and thymidylate synthase--and are actively being evaluated in patients with non-small cell lung cancer. This review will focus on the role of these biomarkers as predictive and/or prognostic markers in the selection of chemotherapy regimens in non-small cell lung cancer patients.