Microbial agents are implicated in each of the most prevalent etiologic hypotheses of Crohn's disease. Although chronic infection with a specific, persistent pathogen cannot be excluded, it is more likely that Crohn's disease is caused by an overly aggressive immune response to normal commensal enteric bacteria. The complex, predominantly anaerobic microbiota in the distal ileum and colon provide a constant source of antigens and adjuvants that stimulate chronic immune-mediated inflammation in genetically susceptible hosts. Host genetic susceptibility in the form of defective mucosal barrier function, bacterial killing or processing can lead to enhanced exposure to luminal bacteria and their immunologically active components, whereas defective immunoregulation can lead to lack of appropriate immunosuppression. Either process can lead to overly aggressive T-cell responses to normal bacteria that causes tissue damage. Transient infection with pathogenic organisms could serve as environmental triggers to initiate inflammatory responses that are perpetuated in susceptible hosts by commensal microbial antigens. In addition, commensal bacteria such as Escherichia coli recovered from the ileum of patients with recurrent Crohn's disease after resection can contain virulence factors that mediate epithelial attachment, invasion, and resistance to killing. Finally, Western diet, antibiotic use, hygiene, and public health practices may have altered the balance of beneficial versus aggressive microbial species. Crohn's disease patients exhibit enhanced humoral and T-cell responses to common commensal bacterial and fungal antigens. These observations may help identify clinically relevant patient subsets and suggest novel therapeutic approaches to restore a beneficial balance of enteric microbiota, enhanced microbial killing, and inhibit aggressive T-cell responses to microbial antigens.