Elevated immune responses to the enteric microbiota have long been associated with inflammatory bowel disease (IBD), especially Crohn's disease. In recent years there has been considerable progress in identifying a number of the specific bacterial and host molecules whose interactions mediate these responses. However, deciphering the role of these interactions in the pathophysiology of IBD remains a difficult challenge, in part due to the very complex nature of the epithelial cell / microbial / immune cell interactions that play a central role in maintaining the gut's well-being. This article reviews such progress and discusses these challenges in the context of focusing on 1 particular protein, bacterial flagellin.