Lung cancer is a common malignancy and is the major determinant of overall cancer mortality in developed countries.1Extensive prospective epidemiologic data clearly have established cigarette smoking as the major cause of lung cancer.2Tragically, despite an impressive body of research that has defined the major risk factors for the disease, little has changed in the management of the disease in the last decade. The mainstay of treatment remains surgical resection of the tumor, and the dismal prognosis of most patients leads to extensive attempts at early detection of malignant lung nodules by low-dose CT scans. However, the effect of these screening efforts on patient survival is still unclear.3The lack of effective therapeutic modalities and the need for better screening methods have led to a very productive search for genes and chromosomal regions associated with lung cancer. An overwhelming number of genes, pathways, and chromosomal regions have been associated with lung cancer. For instance, studies utilizing comparative genomic hybridization analysis have shown nonrandom increases in chromosomal copy numbers of 1p, 1q, 3q, 5p, 6p, 8q, 12, 17q, 19p, 19q, 20p, 20q, and X chromosome regions,4 implying that direct-acting oncogenes relevant to the tumorigenic process reside in these chromosomal regions. Similarly, decreases in chromosome copy number, which are indicative of the involvement of tumor suppressor genes, also have been described in multiple regions, including 2q, 3p, 4p, 5p, 8p, 9p, 10p, 11p, 11q, 13q, and 17p.4 The overexpression or increased function of many oncogenes, including c-Myc, mutated K-ras, EGFR, cyclin D1, and BCL2, has been implicated in the pathogenesis of lung cancer,,2 as well as in the abnormal expression or impaired function of tumor suppressor genes such as, but not only, p53, p16, Rb, FHIT, RASSFF1A, SEMA3B, PTEN, hOGG1, and BAP1.,2 Even a quick glance at the list of regions with chromosomal aberrations and the list of genes involved in lung cancer suggests that the phenotypic changes resulting in lung cancer are caused by alterations in more than one pathway and are probably associated with altered expression levels of multiple and potentially hundreds of genes. Furthermore, it is tempting to hypothesize that the combined effects of these changes in the expression of hundreds of genes explain much of the biological behavior of lung cancer, including the relative resistance to chemotherapy, the aggressive nature of the disease, and the unpredictable prognosis in some patients. Additionally, it may suggest that the focus on single genes as disease markers is almost futile, and that the use of global molecular profiling methods that look at patterns and multiple markers, and not single genes, is probably more likely to generate molecular surrogate tumor markers.