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Pancreatic cancer is a uniformly lethal malignancy with an abundant dense desmoplastic stroma. Because of its dense stroma, conventional drugs were considered to not penetrate this physical barrier, and this caused a systemic drug resistance. Thus, abolishing this barrier with targeted agents is considered to improve the efficiency of chemotherapeutic treatment. The Hedgehog (Hh) signaling pathway is a critical regulator of pancreas development and plays diversified roles in pancreatic cancer stroma and neoplastic cells. Increasing Hh expression in neoplastic cells added desmoplastic stroma accumulation in orthotopic tumors, and Hh inhibitors that target the stroma have an ability to prolong the overall survival of Pdx-1-Cre/KrasG12D/p53R172H mice models via deleting the stromal components and increasing vascularity in pancreatic tumor. However, the failure of translation from bench to bedside indicate the complexity of the relationship between Hh signaling and desmoplastic stroma, and more insights into the complex relationships between Hh signaling pathway and stroma, even tumor cells, might help redesign Hh-targeted therapy. In this review, we discuss the possible mechanism of translation of Hh inhibitor in the clinic from pathology to molecular mechanism.