Since the discovery of tumor necrosis factor TNFalpha about 25 years ago, TNF superfamily has grown to a large family of related proteins consisting of over 20 members that signal through over 30 receptors. Members of this superfamily have wide tissue distribution and play important roles ranging from regulation of the normal biological processes such as immune responses, hematopoiesis and morphogenesis to their role in tumorigenesis, transplant rejection, septic shock, viral replication, bone resorption and autoimmunity. Thus, many approaches to harness the potency of TNF superfamily members to treat human diseases have been developed. Indeed, TNF and TNF agonistic molecules have been approved for human use in the United States and other countries. Many other TNF family members show promise for several therapeutic applications, including cancer, infectious disease, transplantation and autoimmunity. This chapter will give overview of TNF superfamily for exploitation for therapeutic use in humans.