Diseases affecting endodermal organs like the pancreas, lung and gastrointestinal (GI) tract have a substantial impact on human welfare. Since many of these are congenital defects that arise as a result of defects during development broad efforts are focused on understanding the development of these organs so as to better identify risk factors, disease mechanisms and therapeutic targets. Studies implementing model systems, like the amphibian Xenopus, have contributed immensely to our understanding of signaling (e.g. Wnt, FGF, BMP, RA) pathways and gene regulation (e.g. hhex, ptf1a, ngn3) that underlie normal development as well as disease progression. Recent advances in genome engineering further enhance the capabilities of the Xenopus model system for pursuing biomedical research, and will undoubtedly result in a boom of new information underlying disease mechanisms ultimately leading to advancements in diagnosis and therapy.