Crohn's disease is a chronic inflammatory disorder that follows a progressive and destructive course. Ultimately, uncontrolled inflammation leads to bowel damage from disease-related complications such as strictures, fistulas and abscesses and surgical resection. Conventional ‘step-care’, whereby corticosteroids and immunosuppressives are prescribed sequentially, is an incremental approach to treatment that does not prevent disease progression and conveys an important risk of adverse events from repeated courses of corticosteroids. Although the immunosuppressives azathioprine, 6-mercaptopurine and methotrexate are corticosteroid-sparing, they are not highly effective for inducing mucosal healing or preventing disease progression. Tumour necrosis factor antagonists induce and maintain mucosal healing and reduce surgery and hospitalisation rates. This holds out the possibility that long-term use of these agents may prevent bowel damage. Combination therapy with immunosuppressives and tumour necrosis factor antagonists is likely the best strategy for achieving optimal outcomes in patients at high risk of disease progression. However, accurate prognostic markers must be identified to guide patient selection. Long-term prospective studies with robust outcomes are still needed to establish definitively the efficacy and safety of early combination therapy to prevent bowel damage, loss of gastrointestinal tract function and permanent disability.