Smoothened (SMO) is a member of sonic hedgehog homology (SHH) signaling pathway. It plays a key role as a bridge between patched-1 (PTCH-1) and Gli. Aberrant SHH expression can be detected in various malignant tissues, and the expression in pancreatic cancer stem cells is higher apparently. SHH signals are closely associated with self-duplication of cancer stem cells, formation of tumor vessels as well as matrixes. SMO antagonists such as cyclopamine, GDC-0449 and so on show potential to inhibit activity of SHH signaling, and arrest the growth as well as metastases of tumors. Recently, a few of SMO antagonists have been studied in phase I clinical trials and some are in phase II, meanwhile, phase I or II trials of SMO antagonists to treat pancreatic cancer are performed currently. As the classical SMO antagonist, cyclopamine is extracted from a medicinal plant. Perhaps researchers may be able to determine more effective SMO-targeting drugs from herbal medicines in the future.