Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressiveness and resistance to both radiation and chemotherapeutic treatment. To better understand the molecular pathogenesis of pancreatic cancer, DNA array technology was employed to identify genes differentially expressed in pancreatic tumors when compared to non-malignant pancreatic tissues. RNA isolated from 11 PDACs and 14 non-malignant bulk pancreatic duct specimens was used to probe Affymetrix U95A DNA arrays. Genes that displayed at least a fourfold differential expression were identified and real-time quantitative PCR was used to verify the differential expression of selected upregulated genes. Interrogation of the DNA array revealed that 73 genes were upregulated in PDACs and 77 genes were downregulated. The majority of the 150 genes identified have not been previously reported to be differentially expressed in pancreatic tumors, although a number of the upregulated transcripts have been reported previously. Immunohistochemistry was used to correlate calponin and insulin-like growth factor binding protein-5 (IGFBP-5) RNA levels with protein expression in PDACs and revealed peritumoral calponin staining in the reactive stroma and intense focal staining of islets cells expressing IGFBP-5 at the edge of tumors; thus implicating the interplay of various cell types to promote neoplastic cell growth within pancreatic carcinomas. As a potential modulator of cell proliferation, the overexpression of IGFBP-5 may, therefore, play a significant role in the malignant transformation of normal pancreatic epithelial cells.