Although these failed trials were based on sound preclinical evidence supporting a key role of HH/GLI signaling in malignant progression of various cancer entities [119–123], the unforeseeable complexity of HH/GLI signal regulation within the tumor and its microenvironment as well as the frequent development of a priori and/or acquired drug resistance have recently challenged the concept of HH/GLI targeting in oncology [124, 125]. This evidence concerns the gene GLI1 and neoplasm.