The hedgehog (Hh) signaling pathway plays many roles in invertebrate and vertebrate development. For example, specific inhibition of sonic Hh expression is critical during early stages of pancreas organogenesis, but an active Hh pathway appears to be required for maintenance of adult endocrine functions. Mutational inactivation of the Hh pathway has been demonstrated in human malignancies of the skin, cerebellum, and skeletal muscle. Now, two papers implicate aberrant Hh signaling in human upper gastrointestinal cancers including those developing from the esophagus, stomach, biliary tract, and pancreas.