Lung cancer is the leading cause of cancer death in the United States, with 157,000 deaths annually, and in the world, with 1,375,000 deaths annually. 2 The overall 5-year survival for lung cancer remains at 16%, which is signifi cantly lower than the mortality rate for other common cancers, including colon, breast, and prostate cancer. The discrepancy in the mortality rate of lung cancer compared with other cancers has several explanations. First, lung cancers are typically detected at an advanced stage. The anticipated implementation of population-based screening for lung cancer is expected to decrease mortality. Second, compared with the other common cancers that share adenocarcinoma as the histology, lung cancer is heterogenous histologically and biologically. Until recently, lung cancer was treated as a homogenous disease with all nonsmall cell lung cancers (NSCLCs) treated identically, solely on the basis of clinical stage. Based on bench and clinical research, the treatment of lung cancer has been refi ned, with treatments allocated according to histology and specifi c molecular features. For example, targeting mutations such as epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKIs) has been particularly successful as a treatment modality, demonstrating response rates in patients with EGFR-mutated adenocarcinoma that are significantly higher than those for conventional chemotherapy. However, the development of new targeted therapies is, in part, highly dependent on an improved understanding of the molecular underpinnings of tumor initiation and progression, knowledge of the role of molecular aberrations in disease progression, Based on recent bench and clinical research, the treatment of lung cancer has been refi ned, with treatments allocated according to histology and specifi c molecular features. For example, targeting mutations such as epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors has been particularly successful as a treatment modality, demonstrating response rates in selected patients with adenocarcinoma tumors harboring EGFR mutations that are signifi cantly higher than those for conventional chemotherapy. However, the development of new targeted therapies is, in part, highly dependent on an improved understanding of the molecular underpinnings of tumor initiation and progression, knowledge of the role of molecular aberrations in disease progression, and the development of highly reproducible platforms for high-throughput biomarker discovery and testing. In this article, we review clinically relevant research directed toward understanding the biology of lung cancer. The clinical purposes of this research are (1) to identify susceptibility variants and fi eld molecular alterations that will promote the early detection of tumors and (2) to identify tumor molecular alterations that serve as therapeutic targets, prognostic biomarkers, or predictors of tumor response. We focus on research developments in the understanding of lung cancer somatic DNA mutat...