Substantial progress has been made in the last decade toward defining the signaling pathways that can be activated by TNF and identifying the relevant intracellular signaling molecules. The in vivo consequences of targeted disruption of many of the genes encoding proteins involved in TNF signaling (as discussed in this review) are quite different from those observed for knockout mutations of TNF and the TNF receptors (Erickson et al, 1994; Marino et al, 1997; Rothe et al, 1993) that use these molecules. This suggests that there is still much to be learned about the mechanisms for determining specificity in signaling. The ability to specifically manipulate the involvement of these molecules in TNF signaling, without affecting other pathways, may provide new therapeutic approaches to the many diseases in which TNF has a crucial role.