Over the past decade methotrexate has emerged as a new treatment for chronically active Crohn's disease. Although controlled trials to compare the relative efficacy and safety of azathioprine and methotrexate in therapy-resistant patients are desirable, these studies will be difficult, if not impossible, to conduct because of the relatively small differences in potency and tolerability between these agents. A more productive area for future investigations is to explore the use of these drugs in combination with infliximab and other biologic treatments.