Abstract: The Hedgehog (HH) signaling pathway plays an important role in embryonic development, stem cell biology and tissue homeostasis. The aberration of HH signaling pathway is closely related to the development of various cancers. Smoothened (SMO) is the main transducer of the HH signaling pathway and inhibition of SMO can effectively inhibit HH pathway, thereby effectively inhibiting the development of tumors. Up to now, three SMO inhibitors have been approved by U.S. Food and Drug Administration (FDA). However, their clinical application has been limited by drug resistance. The main resistance mechanisms of SMO inhibitors are outlined and the way for future endeavors is pointed.