Prevention of the postoperative recurrence of Crohn's disease (CD) remains a challenging clinical problem. The majority of patients with CD will need surgery for treatment of the disease, most of these patients will develop recurrent symptoms within 5 years postoperatively, and many patients will need reoperation within 10 years. In patients with an ileocolic anastomosis, endoscopic recurrence precedes clinical recurrence and the severity of endoscopic recurrence correlates with the risk of clinical recurrence. Despite multiple studies, the best postoperative prophylactic therapy remains uncertain. Numerous randomized controlled trials of 5-aminosalicylates have shown only modest effect. Antibiotics, including metronidazole and ornidazole, decrease short-term, but not long-term endoscopic recurrence and are limited by side effects. Immunomodulators have yet to be extensively evaluated, although limited data suggest possible efficacy in preventing postoperative recurrence, particularly in high-risk patients. This review will evaluate the current state of the art therapy for postoperative prophylaxis in CD, with an emphasis on critical analysis of the available randomized controlled trials.