The tumor necrosis factor (TNF) is now recognized as one of the most pleiotropic mediators of host defense, immune regulation, and inflammatory response. Due to its broad spectrum of effects, TNF has been implicated as a key mediator in the pathogenesis of acute and chronic inflammatory conditions. The inhibition of bioactive TNF could therefore provide a substantial therapeutic benefit. One approach to a potent TNF antagonist is to use recombinant protein technology in the design of a molecule in which the heavy-chain sequences of an immunoglobulin are fused with the ligand-binding region of the TNF receptor. This paper describes some aspects of the preclinical safety evaluation of the recombinant human TNF receptor-immunoglobulin fusion protein (TENEFUSE). Specific emphasis was placed on transgenic and gene-deleted mice models as central sources of information in the safety evaluation of this TNF antagonist.