The gastrointestinal epithelium is covered by a protective mucus gel composed predominantly of mucin glycoproteins that are synthesized and secreted by goblet cells. Changes in goblet cell functions and in the chemical composition of intestinal mucus are detected in response to a broad range of luminal insults, including alterations of the normal microbiota. However, the regulatory networks that mediate goblet cell responses to intestinal insults are poorly defined. The present review summarizes the results of developmental, gnotobiotic, and in vitro studies that showed alterations in mucin gene expression, mucus composition, or mucus secretion in response to intestinal microbes or host-derived inflammatory mediators. The dynamic nature of the mucus layer is shown. Available data indicate that intestinal microbes may affect goblet cell dynamics and the mucus layer directly via the local release of bioactive factors or indirectly via activation of host immune cells. A precise definition of the regulatory networks that interface with goblet cells may have broad biomedical applications because mucus alterations appear to characterize most diseases of mucosal tissues.