The current model of pathogenesis for inflammatory bowel disease (IBD) is a dysregulated immune system that is triggered by an environmental factor in a genetically susceptible individual. Although much about this model remains unproven, it is believed that bacteria are often the environmental factor driving the inflammatory response. This is supported by indirect evidence that antibiotics are of benefit in the treatment of Crohn's disease (CD) and pouchitis, and observations that enteric infections may result in activation of ulcerative colitis disease activity. In CD, limited studies have demonstrated that metronidazole, ciprofloxacin, and rifaximin improve clinical disease activity, and this is more pronounced in the treatment of colonic disease and for perianal fistulas (with metronidazole and ciprofloxacin). In addition, limited evidence supports the use of metronidazole in the prevention of recurrence after resection in CD. Antibiotics have not shown substantial benefit in the treatment of ulcerative colitis, but a variety of antimicrobial agents have a definite role in the treatment of acute and recurrent or chronic pouchitis. The absence of specifically identified organisms that are primarily responsible for the observed clinical picture remains the challenge to confirming the relationship between bacteria and IBD. A proposal for future therapies is provided that might include a combination therapy aimed at both a reduction in pathogenetic bacteria and immune modulation to achieve the most durable remission of disease.