Lung cancer is the most common malignancy in the United States and worldwide. In 2011, it is estimated that more than 221,000 people in the United States will be diagnosed with cancer of the lung and bronchus. For patients with early-stage disease, 5-year survival approaches only 50%. Recent advances using molecular, genetic, and proteomic profiling of lung tumors have enabled refining the prognosis for patients with non-small cell lung cancer. With targeted therapies, there is an opportunity to enhance long-term survival. This article discusses several key molecular markers used in the prognostication and treatment of non-small cell lung cancer.