Non-small cell lung cancer (NSCLC) can be classified into the major subtypes adenocarcinoma (AC) and squamous cell carcinoma (SCC). Although explicit molecular, histological and clinical characteristics have been reported for both subtypes, no specific therapy exists so far. However, the characterization of suitable molecular targets holds great promises to develop novel therapies in NSCLC. In the present study, global gene expression profiling of 58 human NSCLC specimens revealed large transcriptomic differences between AC and SCC subtypes: more than 1700 genes were found to be differentially expressed. The assignment of these genes to biological processes pointed to the deregulation of distinct sets of genes coding for cell junctions in both tumor subtypes. We focused on 17 cell adhesion genes and 11 reported marker genes for epithelial-mesenchymal transition (EMT), and investigated their expression in matched tumor-normal specimens by quantitative real-time PCR. The majority of the cell adhesion genes was significantly up-regulated in at least one tumor subtype compared to normal tissue, predominantly desmosomes and gap junctions in SCC, and tight junctions in AC. The higher expression of EMT marker transcripts in tumor specimens suggested a large potential for invasion and migration processes in NSCLC. Our results indicate that AC and SCC in the lung are characterized by the expression of distinct sets of cell adhesion molecules which may represent promising targets for novel specific therapies.