The intestinal mucosa has to withstand exposure to a variety of substances, challenges in pH, temperature, and osmolarity; and, finally, bacterial products which might induce local and systemic inflammatory responses. The mucosal integrity is conserved by a defense system which consisting of constitutive and inducible mechanisms. These include the physical barrier function; the secretion of factors into the lumen, such as mucins and antibacterial substances; the mucosal immune system; and, finally, the ability of the mucosa to reconstitute once damage has occurred. The homeostasis and integrity of the gastrointestinal mucosa ultimately depends upon the balance between defensive and aggressive factors. While the physical barrier function was formerly believed to play the major role in mucosal protection against luminal bacteria, the recent discovery of Toll-like receptors and antimicrobial peptides in the intestinal epithelium has modified the concept of intestinal defense towards a more active character, which will be discussed in this review.