Inflammatory bowel diseases (IBD) provide a complex model of host-microbe interactions underpinning disease pathogenesis. Although there is no widespread agreement on the aetiology of IBD, there is evidence that microorganisms lead to the often severe inflammatory response characteristic of the disease. IBD is thought to result from an inappropriate and continuing inflammatory response to pathobionts microbes in a genetically susceptible host. In this review, we discuss the complex microbial ecosystem of the mammalian gut, the underlying genetic factors that predispose to IBD, and how these gene variants may alter host-microbe interactions and propagate inflammation. Incentive should be given to research that will promote a better understanding of host-microbial interactions in the intestine and lay the foundations for new therapeutic approaches to both treat and prevent onset and relapse of intestinal inflammation in genetically susceptible hosts.