TNF superfamily consists of 19 ligands and 29 different receptors. TNF, the first member of the family was discovered about two decades ago as a protein involved in suppression of tumor cell proliferation. Most of them have been found to mediate a wide variety of diseases including cancer, arthritis, bone resorption, allergy, diabetes, atherosclerosis, myocardial infarction, graft versus host disease and AIDS. The signaling mechanism induced by members of this family is becoming increasingly more apparent and serve as a potential target for the development of therapeutics. All the members of the TNF superfamily are known to activate NF-κB, JNK and mediate apoptosis or cell proliferation. The current review focuses on the effects of deletion of genes that mediate the signaling pathways induced by members of TNF superfamily.