The recently described high resolution three-dimensional structures of the transmembrane and the extracellular domains of the human Smoothened (Smo) receptor higlight both conserved and unique structural features of this G protein-coupled receptor. It enables a better understanding of very subtle molecular mechanisms regulating Smo function and demonstrates the very plastic nature of this receptor which is able to accommodate a diverse array of small molecular weight ligands through several binding sites. This structural information should pave the way for designing small molecular weight modulators of Smo function targeting different binding sites and insensitive to clinically observed receptor mutations.