In the last ten years, blockade of the cytokine TNF-alpha has emerged as a powerful new treatment for Rheumatoid Arthritis and related inflammatory disorders. However, differences in efficacy and side effect profiles amongst TNF antagonists have revealed important differences in their mechanisms of action. In addition, TNF is only one of more than nineteen related cytokines in the TNF superfamily, each of which plays a distinct role in immune system homeostasis and function. Blocking agents against other members of the TNF family are in development and hold promise in the treatment of Rheumatoid Arthritis and other autoimmune disorders. Recent progress in the understanding of the biology and effects of antagonizing therapeutically relevant TNF family members will be reviewed.