The Smoothened (Smo) receptor is a key transducer of the Hedgehog (Hh) signaling pathway, which plays a critical role in tissue maintenance and repair. Recent studies have highlighted the therapeutic value of Smo antagonists for treating Hh-linked cancers. Research on Smo agonists indicates that these molecules are important not only for delineating canonical versus noncanonical Hh signaling but also for understanding the role of Smo in physiological and pathological conditions. This review provides an update on the potential therapeutic importance of Smo modulators, and unravels the increasing complexity of its pharmacology with regard to clinical implications.