ErbB2 and ErbB3 receptor tyrosine kinases are key regulators of proliferation, migration, differentiation and cell survival; however, their roles in gastrointestinal biology remain poorly defined. We hypothesized that ErbB2 and ErbB3 promote colon epithelial cell survival in the context of the wound-healing response following colitis. In this study, mice bearing intestinal epithelial-specific deletion of ErbB2 or ErbB3 were treated with dextran sulfate sodium (DSS). Colon sections were examined for injury, cytokine expression, epithelial cell proliferation and apoptosis. Deletion of epithelial ErbB2 did not affect the extent of intestinal injury in response to DSS, whereas deletion of ErbB3 slightly increased injury. However, the roles of both receptors were more apparent during recovery from DSS colitis, in which ErbB2 or ErbB3 epithelial deletion resulted in greater inflammation and crypt damage during the early reparative period. Moreover, loss of ErbB3 prevented normal epithelial regeneration in the long term, with damage persisting for at least 6 weeks following a single round of DSS. Delayed recovery in mice with epithelial deletion of ErbB2 or ErbB3 was associated with increased colonic expression of tumor necrosis factor alpha and increased epithelial apoptosis. Furthermore, epithelial ErbB3 deletion increased apoptosis at baseline and during DSS injury. Additionally, epithelial cell hyperproliferation during recovery was exacerbated by deletion of either ErbB2 or ErbB3. These results suggest that ErbB2 and ErbB3 have important cytoprotective and reparative roles in the colonic epithelium following injury, by promoting colon epithelial cell survival.