To prevent bacterial overgrowth, colonization of the epithelium and subsequent translocation, the gastrointestinal tract maintains an effective mucosal barrier. Besides mucus the most important components of this protective system are epithelial antimicrobial peptides such as defensins, the cathelicidin LL-37, lysozyme, phospholipase A, and proteins with additional antimicrobial properties such as ubiquicidin, ribosomal proteins or histones. Commensal species may tolerate intestinal antimicrobial peptides, for example Bacteroides ssp. or Parabacteroides ssp. as major species in the human colon were highly resistant to the constitutive defensin HBD-1 and only susceptible to the inducible defensin HBD-3. Reduction of disulfide bonds is an important mechanism activating HBD-1. As several studies show, alterations in the expression of antimicrobial peptides directly influence the composition of the intestinal flora. Correspondingly, an increased production of defensins or inhibition of the processing of mouse defensins to their active form led to a quantitative shift of luminal and mucosal bacterial species. On the other hand, microorganisms also modulate the synthesis of host defensins by induction or inhibition of specific peptides. Lactobacilli, the probiotic strain Escherichia coli Nissle and Salmonella enteritica stimulate HBD-2 expression, whereas Shigella flexneri downregulates the synthesis of HBD-1, HBD-3 and LL-37. Thus, the proper balance between the luminal flora and the mucosa is a permanently dynamic, sensitive and host-specific relationship.