Epithelial tissues rely on tightly regulated stem cell populations to sustain self-renewal and repair, with fundamental signaling pathways and molecular mechanisms playing conserved roles across species. While mammalian models, particularly mice, have been widely used to study these processes, the cost, complexity, and ethical considerations associated with these models necessitate complementary approaches. The Drosophila midgut has emerged as a powerful model system for studying epithelial stem cell biology, providing insights into homeostasis, aging, and cancer. The genetic tools, affordability, and rapid experimental timeline of Drosophila make it an ideal system for investigating fundamental principles of epithelial stem cell regulation. Complementary use of Drosophila alongside mammalian in vivo and advanced in vitro models such as organoids has the potential to accelerate discoveries in homeostasis, aging, and cancer biology.