The luminal compartment of the gastrointestinal tract is colonized by a large and highly complex microflora providing not only nutritional advances, but also representing a potential immunological challenge for the host. Under physiological conditions, the immune cells of the colonic mucosa do not defeat the microflora. In contrast, in cases of inflammatory bowel disease (IBD), the intestinal microflora appears to be the target of immune reactivity as demonstrated in various genetic studies and animal models of mucosal inflammation. The mechanisms responsible for the maintenance of this immunological unresponsiveness in the mucosal compartment are still largely enigmatic though recent studies indicate that luminal components might control this peculiar state. The bacterial fermentation product n-butyrate has been identified as such as critical molecule. Apart from its essential nutritional function for colonocytes, an anti-inflammatory activity of this short-chain fatty acid (SCFA) has been recognized in vitro and in vivo. Regarding its molecular mode of action, an interference with transcription factors critical for the production of pro-inflammatory cytokines has been found. This overview discusses the physiological functions of this bacterial metabolite and its emerging role as a potent regulator of mucosal homeostasis. Special emphasis is laid on potential therapeutic implications of SCFA in the treatment of several forms of colitis.