Lung cancer is the leading cause of cancer related deaths in males and females in the United States. Surgical resection remains the only curative therapy for patients with non-small cell lung cancer (NSCLC). Identifying high-risk patients likely to develop cancer within a defined period of time is a clinical and biologic challenge for improving survival in patients with NSCLC. This study aims to use the power of molecular biology to develop and test promising new molecular markers for the identification of patients at risk of developing non-small cell lung cancer. Molecular studies have shown that clonal genetic alterations, e.g. 9p21 deletions, are often present in the lung epithelia of smokers and patients with a previous lung malignancy. This study will examine lung epithelium in smokers with a previous history of lung cancer and controls for the presence of specific chromosomal losses using state of the art techniques. New molecular markers will be developed and confirmed by genome wide SNP microarray analysis in normal appearing, preneoplastic, and malignant lung epithelium. The identified genetic markers will be used to test mucosa at risk in a unique population and develop a profile of genetic changes that predict progression to invasive cancer over a defined period of time. Genetic alterations at critical chromosome loci have been shown to be able to predict the progression of oral precursor lesions to invasive cancer. Our studies will pave the way for the development of similar markers in lung cancer and rapid translation into the clinical setting.