We outline two examples – HH/GLI signaling in pancreatic and colorectal cancer - to emphasize the strict need for a very careful and comprehensive analysis of the oncogenicity of the HH/GLI pathway within the complex interplay of cancer cells with their microenvironment and the immune system, in order to develop multi-modal therapeutic protocols that may be successful in the future treatment of gastric cancer. Here, GLI1 is linked to colorectal cancer.