Infliximab was the first anti-TNF agent to be approved by the US FDA for the treatment of Crohn's disease (CD) in 1998. In the past 10 years, two other agents, adalimumab and certolizumab pegol, have also been approved for the treatment of CD. In the absence of head-to-head comparisons, the efficacy of these agents appear to be similar for the treatment of luminal CD. There are also prospective, randomized, controlled data to support the use of infliximab for the treatment of fistulizing CD and ulcerative colitis, and supportive post hoc data for the use of adalimumab and certolizumab pegol for the treatment of fistulizing CD. Practical matters, such as patient preference regarding the mode of administration, approval by third-party payers and residual patient cost, may actually play a larger role in choosing a particular anti-TNF agent, as efficacy and safety issues are similar for all three. Unfortunately, many patients do not respond, lose response or develop intolerance to anti-TNF treatment. Thus, new therapies are needed. Natalizumab, the first biologic that is not an anti-TNF agent, was FDA-approved in January 2008 for the treatment of CD patients who have failed conventional treatment, including anti-TNF therapy. As we continue to learn more about the pathogenesis of inflammatory bowel disease, novel targets for drug therapy are being developed.