Inflammatory bowel disease (IBD) still presents major challenges to the understanding of its cause, mechanisms of inflammation, and therapeutic choices to control the damaged tissue. Both types of IBD, ulcerative colitis and Crohn's disease, have been known and investigated for over half century but neither one is fully understood nor can be satisfactorily managed. While many gaps in our knowledge still exist, the last two decades have witnessed an unprecedented progress not only in the etiology but mainly in the mechanisms underlying the chronic inflammatory response. The pattern of IBD epidemiology has drastically changed since World War II, with an increased frequency in countries that have adopted a ''westernized'' life style. A parallel and important phenomenon is the continuous drop in age of onset in children. Unfortunately, only few epidemiological clues are available, with the exception of smoking and diet. What in smoking alters the course of IBD is still a mystery and which, among thousands of additives, could represent a risk factor will remain unknown for the foreseeable future. The current emphasis on the study of the enteric flora as the source of potential antigens against which the mucosal immune system reacts appear well justified. The data from animal models appears particularly convincing. Thus, after decades of relying almost exclusively on patient-derived information, numerous animal models are generating precious new information on IBD pathogenesis. In experimental IBD the genetic background of the animal markedly influences the course of the disease, and the same is probably true in humans. The identification of NOD2 as the first mutated gene associated with a subgroup of Crohn's disease patients is the first evidence that genetics are pointing to the right direction for understanding how the environment interacts with genes to cause IBD. For many years immunology has been the main source of scientific information on mechanisms of IBD. Cytokines, chemokines and other soluble factors dominate immunological studies aimed at understanding how different anti-inflammatory and pro-inflammatory mediators are improperly regulated and how immune imbalance can be restored. The extent to which T-cells live or die is also a key determinant of chronicity. In addition to classical immune cells, epithelial, endothelial, mesenchymal and nerve cells are slowly gaining more importance in IBD pathogenesis, as they contribute to the ultimate fate of tissue damage. Medical and surgical therapies are vastly better now that they were only a couple of decades ago, but they are still far from satisfactory. Steroid and aminosalicylates are still the most common drugs after 60 years of use, and it is time to renovate our therapeutic approach to a more effective one. The value of biologicals has been highlighted by the recent success of anti-TNF therapy. Timing of therapy must also change. The concept of the step-by-step approach is slowly fading away, and the idea of an ''all-out'' approach with multiple concomitant drugs early in the disease is gaining credibility. New reports on early aggressive therapies, and the demonstration that early and late experimental IBD are caused by different mechanisms are changing the way we think about managing IBD. Both ulcerative colitis and Crohn's disease will continue to challenge the medical establishment for year to come, but the possibility that IBD can be conquered is more realistic now that never before.