Almost two decades ago, tumor necrosis factor (TNF) was identified as a protein produced by the immune system that played a major role in suppression of tumor cell proliferation. Extensive research since then has revealed that TNF is a major mediator of inflammation, viral replication, tumor metastasis, transplant rejection, rheumatoid arthritis, and septic shock. As of today, 18 different members of the TNF superfamily have been identified, and 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 acquired immune deficiency disease. All the cytokines of the TNF superfamily mediate their effects through the activation of the transcription factor NF-κB, c-Jun N-terminal kinase, apoptosis, and proliferation. Thus, agents that can either suppress the production of these cytokines or block their action have therapeutic value for a wide variety of diseases. In this review, we have elucidated the signal transduction pathways used by the members of the TNF family and the effects of deletion of genes that mediate the pathways. Our current understanding of the signaling pathways for TNF and other family members could serve as a target for the development of therapeutics.