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.