The liver and pancreas arise from a common multipotent population of endoderm cells and share many aspects of their early development. Yet each tissue originates from multiple spatial domains of the endoderm, under the influence of different genes and inductive cues, and obtains different regenerative capacities. Emerging genetic evidence is illuminating the ability of newly specified hepatic and pancreatic progenitors to reverse their course and develop into gut progenitors. Understanding how tissue programming can be reversed and how intrinsic regenerative capacities are determined should facilitate the discovery of the basis of cellular plasticity and aid in the targeted programming and growth of stem cells.