The mucosal surface of the gastrointestinal tract represents a major entry point and ecological niche for many microbes. It forms an important immune barrier, absorbing nutrients, whilst preventing invasion by organisms. Of the extra-ordinarily diverse species that comprise the microbial world, relatively few organisms are able to succeed in breaching this barrier in an otherwise healthy host. The production and secretion of antimicrobial peptides (AMPs) from surface epithelia and circulating immune cells are likely to play a key role in host protection and homeostasis. A number of these peptides are constitutively produced providing resident protection, whereas others are induced during infection and inflammation. In addition to directly eradicating microorganisms, it is becoming increasingly apparent that AMPs are multi-functional with diverse immuno-modulatory properties. This review focuses on three families of AMPs, defensins, cathelicidins, and lysozyme, and discusses their role in mucosal defence.