Several changes of molecular-genetic parameters in lung epithelial cells contribute to tumorigenesis of the non-small cell lung carcinoma (NSCLC). In addition, fibroblasts of the tissue environment (stroma) significantly support NSCLC tumorigenesis. This work demonstrates by two proteins of the S100 family that molecular parameters changed in NSCLC also have diagnostic importance. Early-stage NSCLC is indicated by an increased expression of S100A2 (squamous cell carcinoma) and S100P (adenocarcinoma), respectively. Moreover, application of the novel antibody microarray technology identified an increased level of HDAC (histone deacetylase) 3 in NSCLC. The strongly reduced expression of the cell surface receptor RAGE (receptor for advanced glycation end-products) is as another parameter indicating neoplastic changes in the lung. Detailed studies suggest that the reduced level of RAGE in lung epithelial cells might contribute to tumorigenesis 1) by the loss of the epithelial cell organization and 2) by the improved tumor growth, in particular, due to a higher sensitivity of NSCLC cells towards the growth-promoting effect of adjacent fibroblasts. The growth-promoting effect of fibroblasts is associated with a number of molecular changes in NSCLC cells including the stimulation of protein kinases (p42/44, Akt, p70S6) and a moderately increased level of the pro-tumorigenic factor HMGB (High Mobility Group Box) protein 1. The mitogenic effect of fibroblasts on NSCLC cells is not impaired as a consequence of fibroblasts` senescence. However, senescent fibroblasts induce moderate oxidative stress in NSCLC cells associated with an increase in oxidative defense mechanisms (SOD (superoxide dismutase) 1). It has been demonstrated by the example of RAGE and other parameters that several molecular-genetic changes are associated with NSCLC tumorigenesis, which is additionally influenced by adjacent fibroblasts of the stroma.