Abnormal response to enteric microflora is a critical factor driving bowel inflammation in patients with inflammatory bowel disease (IBD). Mice with genetically engineered mutations have played a central role in both formulating this hypothesis and elucidating the mechanism that normally protect the host from excessive inflammation within the bowel. One emerging theme is the importance of regulation within the innate immune system in protecting from microflora-driven pathology. In this review, I describe how genetically engineered mice have played a crucial role in shaping our conceptual understanding of pathways that regulate the development of chronic bowel inflammation, and furthermore, explore data derived from the study of genetically engineered mice that implicates the fundamental importance of regulation within the innate immune system in the control of this process.