The intestinal epithelium is one the fastest renewing tissues in mammals and is endowed with extensive adaptability. The more traditional view of a hierarchical organization of the gut has recently given way to a more dynamic model in which various cell types within the intestinal epithelium can de-differentiate and function as an alternative source of stem cells upon tissue damage and stress conditions such as inflammation and tumorigenesis. Here, we will review the mechanistic principles and key players involved in intestinal plasticity and discuss potential therapeutic implications of cellular plasticity in regenerative medicine and cancer.