Although the precise etiology of inflammatory bowel disease (IBD) still remains unclear, considerable progress has been made in the identification of cytokine-mediated signaling pathways involved in the inflammatory process. Recent data have clearly shown that these pathways induce augmented intestinal T-cell activation and thus resistance to apoptosis, which is a central process in disease pathogenesis, as it impairs mucosal homeostasis. Therefore, novel therapeutic strategies aim at restoring activated effector T-cell susceptibility to apoptosis in the gut, based on a pathophysiological rationale. This development is best exemplified by the emergence of agents that target the TNF pathway, IL-6 trans-signaling, and the IL-12/IL-23 pathway. These compounds give hope for the development of new strategies aiming at more effective and less toxic therapies for IBD.