Recently, type I interferons IFN-alpha and IFN-beta (IFN-alpha/beta) have been evaluated in pilot clinical trials for the treatment of active ulcerative colitis. However, the underlying mechanisms that may contribute to a potential therapeutic effect are incompletely understood. A new study in this issue demonstrates a protective role for IFN-alpha/beta, induced by activation of a Toll-like receptor 9-dependent pathway, in a rodent model of experimental colitis.