Elafin and its precursor trappin-2 are known for their contribution to the physiological mucosal shield against luminal microbes. Such a contribution seems to be particularly relevant in the gut, where the exposure of host tissues to heavy loads of microbes is constant and contributes to mucosa-associated pathologies. The expression of trappin-2/elafin has been shown to be differentially regulated in diseases associated with gut inflammation. Accumulating evidence has demonstrated the protective effects of trappin-2/elafin in gut intestinal disorders associated with acute or chronic inflammation, or with gluten sensitization disorders. The protective effects of trappin-2/elafin in the gut are discussed in terms of their pleiotropic modes of action: acting as protease inhibitors, transglutaminase substrates, antimicrobial peptides or as a regulator of pro-inflammatory transcription factors. Further, the question of the therapeutic potential of trappin-2/elafin delivery at the intestinal mucosa surface is raised. Whether trappin-2/elafin mucosal delivery should be considered to ensure intestinal tissue repair is also discussed.