The aims of this work were (1) to highlight and to compare a possible SHH/Gli signature between OS and ES, (2) to strengthen our knowledge concerning the role of EWS-FLI1 in the SHH signature in ES and (3) to evaluate the effect of the specific Gli inhibitor GANT61 in vivo on the growth of ES tumors using an orthotopic mice model. The gene discussed is SHH; the disease is Ewing sarcoma.