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Since the advent of the new proteomics era more than a decade ago, large-scale studies of protein profiling have been exploited to identify the distinctive molecular signatures in a wide array of biological systems spanning areas of basic biological research, various disease states, and biomarker discovery directed toward therapeutic applications. Recent advances in protein separation and identification techniques have significantly improved proteomics approaches, leading to enhancement of the depth and breadth of proteome coverage. Proteomic signatures specific for invasive lung cancer and preinvasive lesions have begun to emerge. In this review we provide a critical assessment of the state of recent advances in proteomic approaches and the biological lessons they have yielded, with specific emphasis on the discovery of biomarker signatures for the early detection of lung cancer.