The gastrointestinal epithelium functions as an important physical barrier that separates the rich, diverse, and potentially immunogenic luminal content from the underlying mucosal immune system. In pathological situations such as inflammatory bowel disease, ischemic/hypoxic episodes and bacterial infection, insults to the intestinal epithelium threaten the integrity of the mucosal barrier and represent a huge challenge for the host. During episodes of epithelial injury and barrier breakdown, the host initiates a rapid wound healing response aimed at resealing the gap region and reestablishing homeostasis. This response named "restitution" involves migration of epithelial cells toward the injured regions, as well as epithelial cell proliferation until the gap is closed and the barrier function is reestablished. These biological processes are influenced by a variety of factors derived from the gastrointestinal microenvironment, including host epithelial and lamina propria cells, as well as the microbiota, and the dietary and non-dietary components present in the gastrointestinal lumen. In this manuscript, we will review both host signaling events and luminal factors that influence the wound healing response and have an impact on host homeostasis.