Smoothened (Smo) inhibitors are under intense development for the treatment of cancers linked to abnormal Hedgehog (Hh) signaling. The first inhibitor (vismodegib) was introduced in clinics for basal cell carcinoma and medulloblastomas associated with activating mutations of Hh signaling. In contrast, disappointing data are reported for cancers related to ligand overexpression. Here, we review recent preclinical and clinical data on the potential therapeutic importance of Smo and highlight the complexity of Smo pharmacology and its clinical implications.