Epithelial cells of many mucosal organs have adapted to coexist with microbes and microbial products. In general, most studies suggest that epithelial cells benefit from interactions with commensal microorganisms present at the lumenal surface. However, potentially injurious molecules found in this microenvironment also have the capacity to elicit local inflammatory responses and even systemic disease. In this environment, the epithelium has evolved effective mechanisms to cope with microbial products and to provide appropriate responses to potential pathogens. Although our understanding of these mechanisms is clearly in its infancy, a number of recent findings provide insight into phenotypic characteristics that allow for this discrimination. Here, we briefly review some of these mechanisms, with particular attention to epithelial expression of the anti-infective molecule bactericidal/permeability-increasing protein.