The etiologies of inflammatory bowel diseases (IBD) are not known but are thought to involve a genetic predisposition toward exaggerated inflammatory responses to enteric flora. Effective treatments for IBD are therefore predicated on the regulation of inflammatory responses in the intestine. Most current therapeutic agents for IBD, including 5-ASA, prednisone, and anti–TNF antibody are directed at the reduction of proinflammatory molecules. Recently, a number of negative regulatory molecules (eg, IL-10, TGF-β, CTL antigen-4 [CTLA-4], Fas, suppressor of cytokine signaling [SOCS] proteins, A20, and Src homology protein-1 [SHP-1]), which either bind to effector immune cells and inhibit their activation (eg, IL-10, TGF-β, and CTLA-4), induce programmed cell death (eg, Fas), or regulate intracellular signaling pathways (eg, SOCS proteins, SHP-1, and A20), have been identified. These negative regulatory molecules may provide novel therapeutic targets for the treatment of IBD.