Patients with one of the many chronic inflammatory disorders broadly classified as inflammatory bowel disease (IBD) now have a diverse set of immunomodulatory therapies at their disposal. Despite these recent medical advances, complete sustained remission of disease remains elusive for most patients. The full healing of the damaged intestinal mucosa is the primary goal of all therapies. Achieving this requires not just a reduction of the aberrant immunological response, but also wound healing of the epithelium. No currently approved therapy directly targets the epithelium. Epithelial repair is compromised in IBD and normally facilitates re-establishment of the homeostatic barrier between the host and the microbiome. In this review, we summarize the evidence that epithelial wound healing represents an important yet underdeveloped therapeutic modality for IBD. We highlight three general approaches that are promising for developing a new class of epithelium-targeted therapies: epithelial stem cells, cytokines, and microbiome engineering. We also provide a frank discussion of some of the challenges that must be overcome for epithelial repair to be therapeutically leveraged. A concerted approach by the field to develop new therapies targeting epithelial wound healing will offer patients a game-changing, complementary class of medications and could dramatically improve outcomes. Copyright © 2021. Published by Elsevier Inc.