The lung epithelial surface is one of the vital barriers or sensors in the body responding to the external atmosphere and thereby always subjecting to direct toxicological exposure, stress, stimulus, or infection. Due to its relatively higher sensitivity in response to toxicants, the use of lung epithelial cell culture and lung tissue from animal models or patients has facilitated our learning to lung physiopathology and toxicopharmacology. The recent advancement of proteomics has made it possible to investigate the cellular response at a global level. In this review, the potential applications of proteomic approach in studying lung-related diseases and biomarker discovery will be discussed.