Tumor necrosis factor (TNF) is a central pro-inflammatory cytokine that regulates the expression of numerous signaling pathways implicated in the progression of the immunological reaction. Unraveling the importance of TNF on the pathogenesis of inflammatory bowel disease (IBD) promoted anti-TNF antibodies as novel therapeutic agents. Initially, the main hypothesis behind the clinical application of anti-TNF antagonists in the clinic was that they exert their effects solely through neutralization of TNF. Anti-TNF antibodies induce and maintain clinical remission in patients with minimal side-effects. However, the cellular and molecular mechanisms of actions of the anti-TNF antibodies remain unknown. Various mechanisms of action have been proposed such as activation of transmembrane TNF mediated reverse signaling, induction of apoptosis, pro-inflammatory cytokine down-regulation, complement dependent cytotoxicity, antibodydependent cell-mediated cytotoxicity, and finally activation of regulatory immune cells via interactions with the Fc receptors. The observed discrepancies in the clinical efficacies as well as the differences in the structure of the various TNF antagonists nourish the investigation for additional modes of function.