Commensal bacteria in the lumen of the intestine exist in a mutually advantageous relationship with the mammalian host, providing benefits such as increased metabolic/digestive capabilities and exclusion of harmful microbes, and in turn receiving a nutrient-rich environment. However, in the context of a dysfunctional intestinal epithelial barrier, commensal bacteria may elicit an immune inflammatory response similar to what occurs during infection by a pathogen. Recent work has established that most eukaryotic cells possess families of receptors that can detect the structural signatures of prokaryotic life. Cells may respond to the perception of microbes by activating distinct cytoplasmic signaling cascades that ultimately result in the transcriptional activation of genes needed for proinflammatory and anti-apoptotic functions, as well as for a pro-apoptotic response. Collectively, these responses generally suffice to eliminate microbial threats and may be integral to normal intestinal homeostasis. An understanding of these mechanisms, as well as those by which microbes themselves influence intestinal epithelial responses, may help provide a new perspective on the pathogenesis of intestinal diseases.