The successful introduction of antitumor necrosis factor treatments in clinical practice confirmed the biologic relevance of tumor necrosis factor function in chronic inflammatory conditions in humans, mainly in the pathogenesis of rheumatoid arthritis and inflammatory bowel disease. Studies on patients receiving antitumor necrosis factor treatments offered deeper insights into the mechanisms of antitumor necrosis factor action in arthritis and revealed a master regulatory role for tumor necrosis factor in a multitude of biologic processes underlying pathogenesis. However, within such pleiotropism of key functions, blockade of tumor necrosis factor has also led to a significant incidence of unwanted clinical complications. Experimental work in animal models is providing additional clues on the specific function of tumor necrosis factor and its receptors in disease, especially on the molecular and cellular pathways through which tumor necrosis factor orchestrates beneficial and deleterious responses.