The immune system functions by maintaining a delicate balance between the activities of pro-inflammatory and anti-inflammatory pathways. Unbalanced activation of these pathways often leads to the development of serious inflammatory diseases. TNF (Tumor Necrosis Factor) is a key pro-inflammatory cytokine, which can cause several inflammatory diseases when inappropriately up-regulated. Inhibition of TNF activities by using modulatory recombinant proteins has become a successful therapeutic approach to control TNF activity levels but these anti-TNF reagents also have risks and certain limitations. Biological molecules with a different mode of action in regulating TNF biology might provide a clinically useful alternative to the current therapeutics or in some cases might be efficacious in combination with existinganti-TNF therapies. TNF is also a powerful host defense cytokine commonly induced in the host response against various invading pathogens. Many viral pathogens can block TNF function by encoding modulators of TNF, its receptors or downstream signaling pathways. Here, we review the known virus-encoded TNF inhibitors and evaluate their potential as alternative future anti-TNF therapies.