S100 protein family, representing 25 relatively small calcium binding proteins, has been reported to be involved in multiple stages of tumorigenesis and progression. These proteins are considered having potential value to be adopted as novel biomarkers in the detection and accurate prediction of many kinds of tumors, including lung cancer. As the one having the highest morbidity and mortality among all cancers, lung carcinoma is still occult for detection, especially at early stage. S100 proteins take participation in the lung neoplasia through playing intracellular and/or extracellular functions, therefore getting involved in a variety of biological processes such as differentiation, proliferation, and migration. A few members have also been testified to modulate TGF-β/Smad-3 mediated transcriptional activity of target genes involved in tumor promotion. In addition to that, a number of proteins in this family have already been reported to experience an abnormal trend in lung cancer at cell, serum and tissue levels. Thus, S100 proteins may serve as effective biomarkers for suspected or already diagnosed lung cancer patients. In future, S100 protein family might be applied as therapeutic targets in clinical treatment of lung cancer. In this review, we firstly summed up the biological and clinical evidence connecting S100 proteins and lung cancer, which has not been summarized before.