The epithelial lining of the intestinal tract is highly vulnerable to damage caused by infection and/or inflammation and tumorigenesis. Stem cells that reside within crypts and drive constant homeostatic epithelial renewal throughout life. Upon injury, cells within the epithelium have a remarkable capacity to promote epithelial repair. Regeneration of the intestinal epithelium following damage is dependent on niche signals from surrounding cells that drive epithelial cell plasticity and fetal reprogramming that ultimately leads to replenishment of the epithelium. These same signals are commonly perturbed in disease states and during tumorigenesis where stem cells can promote tumour growth and augment epithelial plasticity in response to chemotherapeutic treatments. Our work utilises conditional genetic mouse models, injury assays and patient-derived intestinal organoids to decipher stem cell dynamics within the epithelium. We also incorporate single cell and spatial technologies to interrogate the molecular mechanisms that control these processes. Our studies have revealed that members of the EGF family of growth factors play a key role in intestinal regeneration and reveal that NRG1 is a potent mediator of changes in epithelial cell fate. We have also defined that reversion to a regenerative fetal cell fate is a key feature of colorectal tumours that are resistant to chemotherapy. This work reveals critical regenerative signals and cell states that could lead to innovative treatment strategies for inflammatory bowel disease and colorectal cancer.