Recent studies have demonstrated that pancreatic adenocarcinoma cells require hedgehog (HH) signaling for proliferation and survival. Mutations in the smoothened (SMOH) gene and loss-of-function mutations in the patched (PTCH) gene, which are involved in the HH signaling pathway, may cause pancreatic tumors. Since HH signaling pathway may contribute to the induction and maintenance of pancreatic tumors, the use of HH pathway inhibitors for targeting the pancreatic cancer might represent a novel therapeutic approach to advanced pancreatic carcinoma. Among the HH inhibitors, cyclopamine inhibits HH signaling through direct interaction with SMOH and retards the growth of cancer cells by inhibiting stem cells. Novel therapies that target the HH signaling pathway should become one of the more effective treatments for pancreatic cancer, which cannot be cured with current therapies.