Adult stem cells reside in many tissues and organs and have the ability to self-renew indefinitely and generate progenies that differentiate and replace aged and damaged cells. Dysregulation of stem cells is intimately associated with various types of diseases such as cancer and degenerative diseases, but the molecular mechanisms regulating stem cell fate decisions during self-renewal and cell lineage differentiation are in general poorly understood. Using intestinal stem cell systems in both flies and mice, we aim to understand the intrinsic and extrinsic mechanisms underlying stem cell fate decisions, and the differentiation and functional regulation of intestinal cells and their roles played in the brain-gut-microbiota axis. Our research should ultimately bring new mechanistic insights into intestinal tumors and other digestive and metabolic diseases and pave the way to new treatments.