Several trials have shown that early treatment of Crohn's disease with immunomodulators and anti-TNF agents leads to a superior clinical outcome, including healing of the mucosa, compared with standard therapy alone. Mounting evidence indicates that mucosal healing is associated with a reduced risk of complications, and a reduced need for surgeries and hospitalizations. In the SONIC trial, a combination of the standard azathioprine immunomodulator therapy and infliximab, an anti-TNF agent, had more potent anti-inflammatory effects than either drug alone in patients with Crohn's disease who had evidence of active inflammation. These findings and those from rheumatoid arthritis trials have prompted the investigation of early initiation of immunomodulator (standard or anti-TNF) therapy for Crohn's disease, in suitable patients, which has led to substantial improvements in disease management. Careful selection of patients is, however, essential given the potential risk of toxic effects from these therapies and the fact that some patients with IBD will have a favorable disease course without them. Identification of suitable patients, however, remains a challenge, as genetic, phenotypic and environmental factors have not yet been identified that can be used for routine assessment and selection is mainly based on clinical criteria.