Although the importance of Hh signaling is now widely recognized across various diseases, and SMO inhibitors have been approved by the US Food and Drug Administration for the treatment of medulloblastoma and basal cell carcinoma,49, 50 some clinical studies shown that SMO inhibition is not always effective, with GLI expression persisting despite SMO inhibition.51, 52 These findings suggest the existence of non-canonical GLI activation, independent of the canonical PTCH-SMO signaling pathway. The gene discussed is SMO; the disease is basal cell carcinoma.