The TNF superfamily of ligands and receptors is critical for mounting innate and adaptive immune responses against foreign pathogens by regulating cell death and survival. Several viruses have recently been shown to induce the expression of death receptor ligands in infected cells, which may serve as an effective strategy for the elimination of cytotoxic T lymphocytes and natural killer cells. In turn, viruses have evolved a variety of strategies to inhibit the effects of death receptor signaling in the infected cells themselves, aiding the progression of replication and dissemination. By contrast, the host has also developed non-lethal antiviral mechanisms initiated by TNF receptor signaling that avoid the potentially costly side-effects of cell death. At the current time, virtually all facets of TNF receptor signaling, from ligand binding to activation of the apoptotic machinery, have been shown to be targeted by viruses.