The present invention relates to compounds, small interfering RNAs and compositions and methods of inhibiting tumorigenesis and methods of inhibiting tumor cell growth and proliferation using agents that inhibit the hedgehog and Gli signaling pathway, including agents that inhibit GLI synthesis and/or function. The present invention also relates to particular biomarkers that can be used in the diagnosis and prognosis of melanomas. Methods of treating cancer, including melanoma are also provided using small organic compounds, siRNAs and blocking antibodies that inhibit or block the SHH/GLI pathway. In addition, the use of agents that inhibit other signaling pathways is contemplated for use as second agents to be used in conjunction with the inhibitors of the GLI pathway.