The natural history of Crohn's disease is characterized by progression to complicated and disabling disease, often necessitating surgical interventions. There is either circumstantial or direct evidence to support the disease-modifying potential of several therapeutic agents. Healing of endoscopic lesions is an emerging surrogate marker of disease modification, as mucosal lesions are considered to reflect ongoing inflammation and tissue damage that lead to the formation of fistulas and fibrotic strictures, which are the main indications for surgery. In contrast to systemic steroids, both azathioprine and anti-tumor necrosis factor (TNF) agents have demonstrated the potential of mucosal healing. Prevention of hospitalization and surgery in the short and medium term has been demonstrated for the anti-TNF agents infliximab and adalimumab. The evidence supporting a role for medical therapy in the prevention of fibrotic wall thickening and in the obliteration of fistula tracks is limited and should be the focus of further prospective studies. These studies should validate predictors of complicated disease and randomized studies should be performed in high-risk groups to investigate whether early introduction of immunosuppressive agents or biologic therapies slows down disease progression and alters the natural history of the disease.