Smoothened (SMO) is a G-protein coupled receptor protein (GPCR-F subfamily) encoded by the SMO gene of the Hedgehog (Hh) pathway. Most often SMO functions during embryonic development, in processes such as digit patterning in the chick limb bud and left–right asymmetry of vertebrate embryos. In addition, Smo function is also fundamental for the maintenance of tissue homeostasis in adults, and deregulated Smo signaling is implicated in tumorogenesis. Hh ligands signal through binding to the membrane receptor Patched (Ptc) to reverse the Ptc-mediated inhibition of signaling by the trans-membrane protein Smoothened (Smo). This allows Smo to activate the intracellular signaling components, resulting in stabilization of down-stream transcriptional activator(s) and activation of target genes.