An unsolved puzzle in IBD research is whether germs, genes, or a combination of the two with excessive immune responses to gut-associated bacteria explains the pathogenesis of UC and CD. Whatever the answer, there is little doubt that microbial factors are involved intimately in IBD pathogenesis. Although a long search has failed to confirm a direct pathogenic role for a specific infectious agent, compelling evidence suggests that commensal enteric bacteria and their products provide a local environmental trigger that initiates and perpetuates IBD, reactivates quiescent disease, results in the frequent septic complications of CD, and contributes to the development of several extraintesinal manifestations. The most compelling evidence for involvement of the enteric flora in the pathogenesis of IBD has been generated from studies of animal models, which collectively support the view that IBD is due to genetically determined dysregulation of the mucosal immune response to luminal antigens derived from the normal bacterial flora. Although removing or dampening the dominant antigenic stimuli with antibiotics or probiotics is conceptually superior to the current array of immunosuppressive and anti-inflammatory agents that nonspecifically block the inflammatory cascade, more definitive, rigorously designed, controlled trials of treatments directed at the microflora are needed. Future research investigating mechanisms of tolerance to luminal bacteria and an understanding of how probiotics can manipulate the intestinal flora beneficially will bring clinicians closer to identifying potential therapeutic targets and unraveling the bacterial connection to IBD pathogenesis.