A detailed understanding of the molecular process involved in the proliferation of pancreatic precursor cells would provide key elements for developing new therapeutic strategies to cure type 1 diabetes. In the present study we investigated the potential involvement of hedgehog signaling in proliferating human pancreatic islet-derived mesenchymal (hPIDM) cells, a population of cells that can be successfully expanded and induced to differentiate into an insulin-secreting phenotype. Here we report that in these precursor cells a hedgehog signaling pathway is activated, as shown by Gli1 expression, and that a dose-dependent inhibition of such a pathway by cyclopamine results in a significant reduction of cell proliferation.