Overactivation of the Hh pathway seen in cancer is a consequence of the following events: (i) excessive production of an Hh ligand resulting in an enhanced auto- as well as paracrine signaling; (ii) somatic mutations in the upstream pathway elements such as SMO and PTCH1; (iii) overexpression of the Hh pathway components (PTCH1, SMO, and GLI1); and (iv) the presence of an alternative splice variant of GLI1–termed truncated GLI1 (tGLI1). Here, SMO is linked to cancer.