Although the advent of infliximab has changed the treatment paradigm and goals in inflammatory bowel disease, it does not provide a cure for it and recent evidence has demonstrated that the immunogenicity of this chimeric anti-tumor necrosis factor antibody is associated with secondary loss of response and intolerance. In ulcerative colitis the efficacy of infliximab was demonstrated in two large clinical trials, but long-term maintenance efficacy data are lacking. Novel biological agents have entered clinical development and pioneering trials have been reported in the last 2 years. For Crohn's disease the fully human IgG1 anti-tumor necrosis factor monoclonal adalimumab, and the humanized anti-alpha4-integrin IgG4 antibody, natalizumab have yielded the most promising results in controlled trials, but also agents inhibiting the crucial interleukin-12/interferon-gamma feedback loop suggest therapeutic potential. For severe ulcerative colitis infliximab has been shown to be an effective rescue treatment and the anti-T-cell CD3 antibody has shown promising open-label results. Crucial in the development of novel biological agents, however, is the benefit:risk ratio. As illustrated by unexpected but devastating brain infections with anti-adhesion molecules, clinicians should be aware that the powerful immunomodulatory capacity of biologicals necessitates a rigorous safety follow-up.