Tumor necrosis factor (TNF)-related cytokines are critical effector molecules in the immune response to viral pathogens. Engagement of the TNF receptors by their cognate ligands activates apoptotic and non-apoptotic signaling pathways, both of which can mediate antiviral activity. In response, viruses have evolved mechanisms to inhibit signaling by some cytokines of the TNF superfamily. These strategies are largely unique to each class of virus, but are similar in that they all target key regulatory checkpoints of the TNF pathway. In recent years, studies directed towards dissecting the mechanisms of TNF signaling and the viral retort have led to several significant discoveries, and form the basis for this review.