Crohn's disease (CD), a form of inflammatory bowel disease (IBD), provides a complex model of host-microbe interactions underpinning disease pathogenesis. Although there is not widespread agreement on the etiology of CD, there is evidence that microorganisms lead to the often severe inflammatory response characteristic of the disease. Despite several microbial candidates, no specific microbe has been considered pathogenic. Instead, the concept of the 'pathogenic community' has emerged from the evidence, whereby the stability of the microbial ecosystem of the healthy human gut is disrupted in response to host genetics and destabilized immunity, perhaps through changing public health practices leading to altered microbial exposures over time. We discuss the complex microbial ecosystem of the mammalian gut, the underlying genetic factors that predispose to CD, and how these gene variants may alter host-microbe interactions and propagate inflammation. Over the next 5 years, the increased understanding of genes involved in CD and the way in which individuals with variants of these genes respond differently to nutrients and drugs will enable the rational development of personalized therapies, using pharmacogenomic and nutrigenomic approaches.