The gastrointestinal tract has the physiologic function of digestion and absorption of food and nutrients. These functions must be balanced with prevention of injury, infection, or inflammation associated with physical, chemical, or pathogenic challenge. Due to its large surface area and exposure to a variety of pathogens, the gastrointestinal tract is an important target for pathogen colonization. Several immune mechanisms exist in the colon to resist against or clear established intestinal infections. Secretion of the MUC2 mucin glycoprotein by colonic goblet cells generates a mucus layer that acts as a physical barrier to pathogen penetration. Equally important, a continuous layer of intestinal epithelial cells, held together by tight junction proteins, prevents the penetration of microbial pathogens into the underlying lamina propria. The mucus layer is expected to contain an array of antimicrobial peptides secreted by intestinal epithelial cells, including cathelicidin. Cathelicidin possesses both direct antibacterial and immunomodulatory functions. Although cathelicidin has well defined immunomodulatory roles in leukocytes, its role in modulating intestinal epithelial cell responses is less understood. Mice deficient in cathelicidin (Camp-/-) had impaired goblet cell secretory responses during infection with C. rodentium, corresponding to increased bacterial load and colonization of the epithelium. Colonic goblet cells in Camp-/- mice were swollen with a retained number of mucin granules, and showed altered mucus secretion during C. rodentium infection. Human cathelicidin, LL-37, induced secretion of two goblet cell proteins, TFF3 and RELMβ, in human colonic epithelial goblet-like (LS174T) cells, an effect that was dependent on reactive oxygen species production. While Camp-/- mice did not display altered intestinal barrier function, stimulation of human colonic epithelial (T84) cells with LL-37 resulted in a temporary increased permeability via the endocytosis and degradation of the tight junction proteins occludin and claudin-2. Collectively, these data establish immunomodulatory functions of cathelicidin acting on the colonic epithelium that contribute to clearance of intestinal bacterial infections.