Oral tolerance is a long-recognized method of inducing immune tolerance or systemic hyporesponsiveness induced by feeding protein. Oral tolerance has been used to prevent and/or treat a variety of T-cell-mediated autoimmune disorders. Feeding colonic extracts prevented colitis in animal model of inflammatory bowel disease (IBD), but the clinical efficacy of oral tolerance in human IBD was unknown. In this issue, the study by Margalit and colleagues suggested that oral administration of autologous colonic extracts to moderately severe Crohn's disease patients might reduce disease activity; however, the study did not employ conventional clinical endpoints. These data provide an important first step to developing "Ag-specific" treatment strategies for IBD in the future. Larger scale studies using variable dosages, modes, and durations of Ag delivery will be required to optimize oral tolerance therapy in IBD.