Open AccessThe hedgehog pathway is a major regulator for cell differentiation, tissue polarity and cell proliferation in embryonic development and homeostasis in adult tissue. Studies from many laboratories reveal activation of this pathway in a variety of human cancer, including basal cell carcinomas, medulloblastomas, leukemia, gastrointestinal, lung, ovarian, breast and prostate cancers. It is thus believed that targeted inhibition of hedgehog signaling may be effective in treatment and prevention of human cancer. Even more exciting is the discovery and synthesis of specific signaling antagonists for the hedgehog pathway, which have significant clinical implications in novel cancer therapeutics. In this review, we will summarize major advances in the last two years in our understanding of hedgehog signaling activation in human gastroesophageal cancer, and their potential in clinical treatment with hedgehog pathway inhibitors.