The gastrointestinal tract serves as a fast-renewing model for unraveling the multifaceted molecular mechanisms underlying remarkably rapid cell renewal, which is exclusively fueled by a small number of long-lived stem cells and their progeny. Stem cell activity is the best-characterized aspect of mucosal homeostasis in mitotically active tissues, and the dysregulation of regenerative capacity is a hallmark of epithelial immune defects. This dysregulation is frequently associated with pathologies ranging from chronic enteritis to malignancies in humans. Application of the adult Drosophila gastrointestinal tract model in current and future studies to analyze the immuno-physiological aspects of epithelial defense strategies, including stem cell behavior and re-epithelialization, will be necessary to improve our general understanding of stem cell participation in epithelial turnover. In this review, which describes exciting observations obtained from the adult Drosophila gastrointestinal tract, we summarize a remarkable series of recent findings in the literature to decipher the molecular mechanisms through which stem cells respond to nonsterile environments.