Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies, with an overall life expectancy of 6 months. Despite considerable advances in the understanding of the molecular mechanisms involved in the carcinogenesis of PDAC, the outcome of the disease was not significantly improved over the last 20 years. Although some achievements in molecular-targeted therapies have been made (that is, targeting the epidermal growth factor receptor by erlotinib), which already entered clinical settings, and despite the promising outcome of the FOLFIRINOX trial, there is an urgent need for improvement of the chemotherapy in this disease. A plethora of molecular alterations are thought to be responsible for the profound chemoresistance, including mutations in oncogenes and tumor suppressors. Besides these classical hallmarks of cancer, the constitutive or inducible activity of transcription factor pathways are characteristic changes in PDAC. Recently, three transcription factors—nuclear factor -κB (NF-κB), nuclear factor of activated T cells (NFAT) and nuclear factor-E2-related factor-2 (Nrf2)—have been shown to be crucial for tumor development and chemoresistance in pancreatic cancer. These transcription factors are key regulators of a variety of genes involved in nearly all aspects of tumorigenesis and resistance against chemotherapeutics and death receptor ligands. Furthermore, the pathways of NF-κB, NFAT and Nrf2 are functional, interacting on several regulatory steps, and, especially, natural compounds such as curcumin interfere with more than one pathway. Thus, targeting these pathways by established inhibitors or new drugs might have great potential to improve the outcome of PDAC patients, most likely in combination with established anticancer drugs. In this article, we summarize recent progress in the characterization of these transcription-factor pathways and their role in PDAC and therapy resistance. We also discuss future concepts for the treatment of PDAC relying on these pathways.