Numerous recent investigations have pointed to a key role of the proinflammatory, pleiotropic cytokine tumor necrosis factor-alpha (TNF-alpha) in host defense and inflammatory processes. TNF overexpression has been found in lesional skin and in the circulation of psoriatic patients, and it was suggested that TNF-alpha is crucial in this and other immune diseases. Several approaches to inhibit TNF-alpha activity have been developed. These include three different neutralizing antibodies to TNF-alpha as well as three different soluble TNF-alpha receptors with characteristic properties designed to bind the 17-KDa soluble trimeric TNF-alpha and the 26-KDa membrane-bound form of TNF-alpha. Clinical trials have demonstrated significant antipsoriatic effects, and it is likely that blocking TNF-alpha will become an important therapeutic option. The data available from these trials contribute to further understanding of the disease by demonstrating the major role of TNF-alpha. An in-depth understanding of the regulation of TNF gene expression, protein production, receptor expression, and signaling pathways may lead to further, potentially important novel therapeutic strategies and antipsoriatic active small molecules, suitable for oral application in the future. Here we review the current knowledge of TNF biology, the approaches to inhibit TNF activity, and their clinical and immunological effects in psoriasis. In addition, the host-defense effects and chronic TNF-blocking activity are discussed.