TNF exerts its biological activities through two distinct receptors of TNF-R55 and TNF-R75. Recent studies have identified TNF receptor-associated molecules, and intracellular signal transduction for apoptosis induced by TNF has been elucidated. Various TNF mutants with higher affinity to TNF-R55 and lower affinity to TNF-R75 are being clarified biogenetically. These mutants show lower adverse effect and higher antitumor activity. Furthermore, TNF gene transduction into lymphocytes and tumor cells shows a decrease in tumorigenicity and enhancement of host immunogenicity. This approach appears to be promising for cancer treatment.