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Natural history studies provide invaluable data on the disease course. First, they help define the end points for clinical trials that are designed to test drugs for the end point of disease modification in chronic disabling diseases. Natural history studies can also help to identify subsets of patients in whom the disease prognosis can be stratified according to clinical features. This comprehensive review summarizes our current knowledge of the natural history of Crohn's disease in adults as reported in population-based studies that include long-term follow-up results.We conducted a literature search of English and non-English language publications listed in the electronic databases of MEDLINE (source PUBMED, 1935 to December 2008).One-third of the patients had ileitis, colitis, or ileocolitis at the time of diagnosis. Disease location remained broadly stable over time. Up to one-third of the patients had evidence of a stricturing or penetrating intestinal complication at diagnosis, and half of all patients had experienced an intestinal complication within 20 years after diagnosis. Ten percent of the patients had prolonged clinical remission. Steroid dependency occurred in one-third of the patients, and surgery was required in one-third after initiation of steroid therapy. The annual incidence of hospitalizations was 20%. Half of the patients required surgery within 10 years after diagnosis. The risk of postoperative recurrence was 44–55% after 10 years.Crohn's disease is a disabling condition over time. The impact of changing treatment paradigms with increased use of immunosuppressants and biological agents on its natural history is poorly known.