During the last few decades it has become increasingly evident that inflammatory bowel disease (IBD) is associated with abnormalities of systemic and mucosal immunity. This association has slowly moved from the phenomenological to the mechanistic level, and today there is solid evidence that the immune system mediates inflammation and tissue damage in the gut of patients suffering from IBD. However, the exact mechanisms of injury and what triggers such mechanisms are yet to be understood in spite of expanding knowledge of the cellular and molecular events underlying gut inflammation. Phenomena detected in the peripheral blood of IBD patients reflect some, but not all, of the events occurring in the gut and have limited meaning. On the contrary, the investigation of phenomena occurring in the inflamed mucosa has yielded valuable information on which progress in the understanding of IBD pathogenesis and the development of new therapies are currently based. It seems that all immune and non-immune components of the mucosa are involved in IBD, either directly or indirectly, as shown by abnormalities of humoral and cell-mediated immunity, cytokine and growth factor, eicosanoids, neuropeptides, reactive oxygen and nitrogen metabolises, cell adhesion molecules, apoptosis, and non-immune cells. Because of the multiplicity and complexity of the interactions of all these elements it is presently impossible to discern between primary and secondary, and pathogenic and non-pathogenic phenomena. In spite of these difficulties, an impressive amount of information is being gathered which is translated, at times in a preliminary or empirical fashion, into novel immunopathology-based forms of treatment.