Despite an increasing use of immunosuppressants and anti-tumor necrosis factor (TNF) agents, approximately half of the patients with Crohn’s disease will require surgery within 10 years after diagnosis. Postoperative relapse is frequent and should be systematically assessed within the first year by endoscopy. Absence of prophylactic treatment is associated with a higher risk of relapse. Other risk factors include smoking, prior intestinal surgery, penetrating disease behavior, perianal location, and extensive small bowel resection. Pooled data indicate that 5-aminosalicylic acid and thiopurines have only slight efficacy to prevent postoperative recurrence in Crohn’s disease. Nitroimidazole antibiotics are modestly effective, but long-term toxicity limits their use in clinical practice. Recently, anti-TNF agents in this setting have demonstrated efficacy and dramatically contrast with other interventions, but rising costs are concerning. Anti-TNF agents are highly effective in the prevention of postoperative recurrence in these patients. A therapeutic strategy based on a risk stratification of patients, with further treatment step-up and adjustment if relapse occurs on the basis of ileocolonoscopy, is recommended in clinical practice. Should we move towards top-down strategies based on a wider use of anti-TNF agents even in patients who are not at high risk of postoperative recurrence? Ongoing clinical trials addressing this issue will dramatically change our clinical practice.