The mechanisms of action of antitumor necrosis factor α (anti-TNF-α) antibodies in the therapy of inflammatory bowel disease (IBD) are not completely understood. Binding of antibodies to transmembrane TNF-α seems to be crucial for the induction of several cellular responses, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and reverse signaling. However, these processes alone do not fully explain the diversity of responses to anti-TNF-α therapy seen in different patients. Thus, the present review aimed to discuss the current role of anti-TNF-α antibodies in treatment algorithms for IBD as well as the current knowledge on the mechanisms of action of these antibodies, particularly the less well known aspects of anti-TNF-α blockade. We also discussed a complex role of particular macrophage subpopulations, T regulatory cells, and intestinal endothelial cells, as well as presented new data on the clinical relevance of anti-inflammatory responses attributed to the Fc region of anti-TNF-α antibodies.