Esophagus cancer (EC) can be divided into two major histological categories, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). Although the incidence of ESCC has declined or remained unchanged in the Western world, the incidence of EAC has risen dramatically (350%) in the past 30 years, more rapidly than any other cancer. In contrast, in Asia, EAC is still rare, and ESCC remains the more prevalent cancer of the esophagus. The etiology difference between these two types of esophagus cancers is not clear and a collaborative investigation between the U.S. and Asian investigators to decipher the differences in the types of esophagus cancers is interesting and vital. The Hh/Gli pathway is frequently activated in both EAC and ESCC and is a potential therapeutic target. However, several pathways, independent of Hh can also activate Gli1 (the non--‐canonical Hh pathway). The mechanisms that activate Gli1 through the non--‐canonical Hh pathway are not yet clear. Tumors with activated non--‐canonical Hh pathways are unlikely to respond to the Hh inhibitors even when Gli1 is activated.