The introduction of infliximab, a mouse/human chimeric monoclonal antibody to tumor necrosis factor (TNF), is an important advance in the treatment of Crohn's disease. Infliximab is effective for induction and maintenance of remission in patients with inflammatory luminal and fistulizing disease. The development of human antichimeric antibodies (HACAs) has led to infusion reactions and loss of efficacy in patients treated with infliximab. Strategies to reduce the frequency of HACA formation include induction of immunologic tolerance with a three-dose regimen at 0, 2, and 6 weeks followed by systematic maintenance dosing every 8 weeks; concomitant immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate; and premedication with intravenous corticosteroids. Humanized or fully human anti-TNF biotechnologic agents, including CDP571, CDP870, etanercept, adalimumab, and onercept, are theoretically less immunogenic than the chimeric antibody infliximab. Etanercept is not effective for Crohn's disease. CDP571 is not effective in unselected patients with active Crohn's disease, but it may be effective in patients with elevated C-reactive protein. The efficacy of CDP870, adalimumab, and onercept is under investigation. The different mechanisms of action of these anti-TNF agents may account for their variable efficacy. Their benefits, however, must be considered in the context of their risks, including infusion reaction; delayed hypersensitivity-like reaction; new onset of autoimmunity, with rare cases of drug-induced lupus and new-onset demyelination; and the potential for rare but serious infections.