The survival data of patients with ductal pancreatic adenocarcinoma are rather poor, partly because the disease is frequently diagnosed at an advanced stage, partly because it is characterized by a chemoresistant phenotype. Even first-line chemotherapeutic drugs result in a modest objective response. This drug resistance is attributed to many different, unrelated mechanisms, including abnormal membrane receptor transport, ineffective metabolic drug conversion or enhanced metabolite inactivation, increased DNA repair and alterations in the apoptotic pathways. The role of NF-kappaB, cyclin D1 and stromal factors is also emphasized by many groups. The involvement of the ABC-transporters is not a universal feature, their alterations are important only in the resistance against specific cytostatics. Although several well-known molecular mechanisms have been elucidated, our understanding of drug insensitivity is still fragmentary, especially because recent microarray studies revealed that hundreds of genes are up- or down-regulated in resistant tumor cells, but their exact significance is still unclear. The reversal of the drug resistance is an area of intensive investigation, but to date, the compounds investigated are effective mainly in experimental systems and prospective studies are needed to validate their clinical applicability.