TNF-α is a crucial pro-inflammatory and immunregulatory cytokine that is central to the pathogenesis of various inflammatory and autoimmune conditions. A number of controlled trials have shown effectiveness for TNF-α inhibitiors in several diseases, in particular rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Crohn's disease. These agents may also be useful in additional autoimmune conditions. The introduction of TNF-α inhibitors has revolutionized the therapeutic approach and treatment paradigms especially for patients with rheumatoid arthritis. Despite extensive investigation, the full profile of their mechanisms of action remain incompletely understood. Optimal use of these agents requires consideration of their possible adverse effects. In addition to the presently available TNF-α blockers, other agents targeting this key mediator are under study. Recent advances and future directions in anti-TNF-α therapy are discussed in this paper.