Objectives: Pancreatic cancer has a very poor prognosis. There has been no improvement in the clinical outcome for several decades. Mature ductal epithelial cells from normal pancreas are unique because they express an array of carbonic anhydrases (CAs), ion channels and transporters that allow for copious secretion of HCO₃^-. This could have major implications for pH_i and pH_e regulation and thereby impact on tumour progression since membrane proteins involved in ion transport control many "hallmarks of cancer". So far, there is little information available on the role of these proteins in pancreatic cancer. We describe experiments to elucidate the role of these membrane proteins in pancreatic tumour progression. Methods: We used several pancreatic cancer cell lines, primary human pancreatic adenocarcinoma samples as well as orthotopic implants of human pancreatic cell lines into immunodeficient mice. Expression and function of transport proteins was assessed by PCR, Western blot, immunohistochemistry, ionic imaging, patch clamp techniques and video microscopy. Results: Pancreatic cancer cells express many proteins involved in ion transport that had been linked to tumour progression, e.g. pH-regulatory proteins NHE1, NBCn1, CA IX, K⁺ channels K_Ca3.1, EAG, hERG and store-operated Ca²⁺ channel components. NHE1 and CA IX are upregulated by hypoxia-inducible factor. Extensive CA IX staining in sections of mouse duodenum and stomach showed high metastatic potential of pancreatic cancer cell lines. NHE1 and K_Ca3.1 blockade impair pancreatic cancer cell migration on defined extracellular matrices. Digestion of the extracellular matrix is attenuated by NHE1 inhibition. Conclusion: The experiments show that pancreatic cancer cells functionally express a number of transport proteins whose pathophysiological importance in tumour progression is well established. Hence, these membrane proteins could constitute a new class of therapeutic targets for pancreatic cancer.