Ulcerative colitis and Crohn’s disease are chronic disabling lifelong diseases which may be disturbed by severe flares and anatomical complications requiring surgery. Until the very last years there was no clear indication that treatment was able to modify the long-term natural history of the disease. In particular, there are no data demonstrating a clear improvement through the period 1950–2003 in disease activity, occurrence of complications and need for surgery, in spite of an increased use of immunosuppressants since the 1990s. However, in inflammatory bowel disease, both thiopurines and methotrexate are very efficient in about one half of the patients, and in responders, may heal the mucosa and decrease the need for surgery. The early use of immunosuppressants in selected patients may have an impact on occurrence of severe flares and complications, and need for surgery. Moreover, anti-TNF now used for 10 years in Crohn’s disease and for 5 years in ulcerative colitis demonstrated in two thirds of the patients a remarkable anatomic effect, healing the mucosa, closing fistulae and preventing strictures. Infliximab does prevent endoscopic recurrence following ileal resection for Crohn’s disease. Actually, because irreversible anatomical damage may develop during the first years of disease, there is a need to classify early in the course of the disease patients who will benefit from anti-TNF and classical immunosuppressants, respectively. There is the need in the next few years to better define these subgroups and to compare different strategies within each group through randomized interventional studies.