Pancreatic cancer, due to its late diagnosis, is difficult to treat. In addition, current therapy options are insufficient and new approaches for combination treatment are required. Recent demonstration of the importance of constitutive signaling of NF-κB-inducing kinase (NIK, also named MAP3K14) in maintaining the high basal activity of the alternative NF-κB pathway in pancreatic cancer suggests novel possibilities for therapeutic intervention. Strategies to target the alternative NF-κB pathway include not only the use of small molecule inhibitors for NIK and IκB kinase α (IKKα), but also broad spectrum approaches such as using proteasome inhibitors or combinatorial approaches targeting both alternative and canonical pathways. These may also act synergistically with currently used drugs.