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Pancreatic cancer is one of the leading causes of cancer mortality in the United States. Current therapy for pancreatic cancer involves surgery, chemotherapy, and radiation therapy; however, the 5-year survival rate remains less than 5%. New strategies for treating pancreatic cancer include targeting intracellular signaling that provides survival advantages to cancer cells. One of these targets is the transcription factor nuclear factor (NF) kappaB, which is activated by a variety of mechanisms. Data demonstrate that increased NF-kappaB activity can promote growth and tumorigenesis, inhibit apoptosis, promote angiogenesis, promote invasion and metastasis, and promote chemoresistance in pancreatic cancer. This review explores the roles of NF-JB in these processes and examines the evidence that different NF-kappaB-inhibiting drugs can improve the treatment of pancreatic cancer.