The complexity of inflammatory bowel disease (IBD) is well recognised at both the clinical and therapeutic levels. Even more complex however appears to be the unravelling of its aetiology and pathogenesis where environmental, genetic, bacterial, and immune factors come together to generate the clinical entities we recognise as Crohn’s disease (CD) and ulcerative colitis (UC).^1,2 When facing a complex problem, a wise approach is to select first its most obvious part, break it down into its various components, and then try to understand the contribution of each component to the problem. IBD is a chronic inflammatory process and therefore inflammation is the fundamental issue, the mechanism responsible for the tissue damage in CD and UC. If chronic inflammation is the central mechanism, what are its components? To keep the answers simple, one can envision a triggering event that initiates IBD, and a number of subsequent events that maintain inflammation and perpetuate IBD. The initial trigger is probably far more dependent on genetics and environmental factors than the events that perpetuate IBD.^3,4 These are more likely to be tissue dependent events and there is little doubt that dysregulation of the local immune response is what underlies gut inflammation and allows it to persist unabated year after year.⁵ Thus until genetic and environmental factors are fully identified, it seems worthy to investigate the various biological systems that contribute to the chronicity of gut inflammation. The purpose of this review is to discuss one key contributor, the CD40/CD40 ligand (L) system, and present evidence that this system plays a major role in immunity and inflammation, can foster chronic inflammation, is directly relevant to IBD, and its modulation may offer therapeutic benefits to IBD patients. To achieve these aims, it is vital to first understand where the CD40/CD40L system …