A surprising number of apparently unrelated human diseases, including familial and sporadic cancers and a number of syndromes and malformations, seem to be associated with abnormal function of the Hedgehog (Hh) signaling pathway. Zinc-finger transcription factors of the Gli family play critical roles in the mediation and interpretation of Hh signals. Elucidating how Gli proteins work will enable us to further our knowledge of how cells proliferate, differentiate or survive in response to Hh signals, as well as to design rational therapies for these Hh-signaling related diseases (HSDs).