Regulation of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/Rel transcription factors (TFs) is extremely cell-type-specific owing to their ability to act disparately in the context of cellular homeostasis driven by cellular fate and the microenvironment. This is also valid for tumor cells in which every single component shows heterogenic effects. Whereas many studies highlighted a per se oncogenic function for NF-κB/Rel TFs across cancers, recent advances in the field revealed their additional tumor-suppressive nature. Specifically, pancreatic ductal adenocarcinoma (PDAC), as one of the deadliest malignant diseases, shows aberrant canonical-noncanonical NF-κB signaling activity. Although decades of work suggest a prominent oncogenic activity of NF-κB signaling in PDAC, emerging evidence points to the opposite including anti-tumor effects. Considering the dual nature of NF-κB signaling and how it is closely linked to many other cancer related signaling pathways, it is essential to dissect the roles of individual Rel TFs in pancreatic carcinogenesis and tumor persistency and progression. Here, we discuss recent knowledge highlighting the role of Rel TFs RelA, RelB, and c-Rel in PDAC development and maintenance. Next to providing rationales for therapeutically harnessing Rel TF function in PDAC, we compile strategies currently in (pre-)clinical evaluation.