The intestinal epithelium is the first line of defense and acts as an interface between the vast microbial world within the gastrointestinal tract and the body's internal milieu. The intestinal epithelium not only facilitates nutrient absorption but also plays a key role in defending against pathogens and regulating the immune system. Central to maintaining a healthy epithelium are intestinal stem cells (ISCs), which are essential for replenishing the intestinal epithelium throughout an individual's lifespan. Recent research has unveiled the intricate interplay between ISCs and their niche, which includes various cell types, extracellular components, and signaling molecules. In this review, we delve into the most recent advances in ISC research, with a focus on the roles of ISCs in maintaining mucosal homeostasis and how ISC functionality is influenced by the niche environment. In this review, we explored the regulatory mechanisms that govern ISC behavior, emphasizing the dynamic adaptability of the intestinal epithelium in the face of various challenges. Understanding the intricate regulation of ISCs and the impact of aging and environmental factors is crucial for advancing our knowledge and developing translational approaches. Future studies should investigate the interactive effects of different risk factors on intestinal function and develop strategies for improving the regenerative capacity of the gut.