Total parenteral nutrition (TPN), or the complete absence of enteral nutrients, is commonly used in a clinical setting. However, a major consequence of TPN administration is the development of mucosal atrophy and a loss of epithelial barrier function (EBF); and this loss may lead to an increase in clinical infections and septicemia. Our laboratory has investigated the mechanism of this TPNassociated loss of EBF using a mouse model. We have demonstrated that the mucosal lymphoid population significantly changes with TPN, and leads to a rise in IFN-γ and decline in IL-10 expression -both of which contribute to the loss of EBF. Associated with these cytokine changes is a dramatic decline in the expression of tight junction and adherens junction proteins. This article discusses the potential mechanisms responsible for these changes, and potential strategies to alleviate this loss in EBF.