Although the cause of Crohn's disease remains obscure, considerable progress has been made in recent years in unraveling the pathogenesis of the inflammatory processes seen in chronic idiopathic inflammatory bowel diseases. Th-1 lymphocytes seem to orchestrate the inflammation through the production of proinflammatory cytokines such as interferon-gamma, interleukin-1 beta, and tumor necrosis factor (TNF) alpha. Since the isolation and characterization of TNF and its two receptors detailed regulatory processes for transcription, secretion, and postreceptor actions of TNF are now rapidly being discovered. Genetically engineered monoclonal antibodies specifically directed against TNF-alpha are only the first drugs acting against TNF, available for clinical use now in the treatment of Crohn's disease. A single intravenous injection of these mono-antibodies produce very dramatic clinical, endoscopic, and histological responses in most refractory patients. More data on long-term safety, efficacy (mainly after repeated infusions) and the exact role in combination with standard therapies are awaited. Until then these drugs should be reserved for patients not responding to standard immunomodulatory therapy and not amenable to surgery. The exciting "TNF story" very nicely illustrates how the benchmark of basic immunological research now provides us with very potent and rationally designed drugs. Careful monitoring of safety of repeated and long-term use of these agents, interfering with very basic physiological events, is mandatory.