The gastrointestinal (GI), pancreatic, and hepatic systems work in concert to break down and absorb nutrients, maintain homeostatic glucose levels, and purify the entire bodily organism. Unfortunately, these systems are plagued by many debilitating and life-threatening diseases. Stem cell-based tissue regeneration holds promise for treating diseases of the digestive system, thereby improving patient health and quality of life. To this end, it is of great importance to understand the developmental mechanisms of organ generation and regeneration, what characterizes stem cells in vivo, and how the microenvironments of the pancreas, liver, and/or intestines regulate self-renewal, proliferation, and differentiation of adult stem cells.