Abstract: Elevated Hedgehog (Hh) pathway activity, including ligand stimulated Hh pathway activity, was detected in digestive tract cancers, including esophagus, stomach, biliary tract, and pancreatic cancer, and determined to be associated with growth and proliferation of the cancer cells. Accordingly, methods are provided for treating a digestive tract cancer associated with elevated Hh pathway activity by reducing or inhibiting the Hh pathway activity. Also provided are methods of determining the responsiveness of a digestive tract tumor to treatment with an Hh pathway antagonist.