Sonic Hedgehog (Shh) pathway regulates embryonic development of different organs including the thyroid gland. The aberrant activation of Shh signaling has been found in several types of cancer and according to recent evidences it represents an important regulator of tumor-stroma interaction. In this study, we have analyzed expression, activation and molecular mechanisms regulating the Shh pathway and its involvement in the modulation of tumor stroma interaction in anaplastic thyroid cancer (ATC) cells. Our results suggest that Shh signaling undergoes a dual mechanism of induction in ATC cells: 1) a basal non-canonical Smo-dependent activation of Gli transcription factor that is partly caused by interaction with the RAS/BRAF/MEK oncogenic pathway and is characterized by the absence of Shh ligand expression in thyroid cancer cells and 2) a paracrine response of cancer cells to Shh ligand secreted by tumor stroma (fibroblasts and mesenchymal stromal cells, MSCs) inducing cancer cell migration and in vitro tumorigenesis. Our data therefore suggest Shh as a potential novel therapeutic target in aggressive thyroid cancers.