Tumor Necrosis Factor (TNF) is one of the many cytokines that comprise a complex intertwined network of biological response modifiers that takes on extreme significance as the host response to infectious diseases. Soluble factors such as Interleukin-2 and Interferon-gamma released by T cells and Interleukin-1, Interleukin-6 and TNF released by monocytes have been shown to play key roles in proliferation, activation and differentiation of immune cells. It has also become evident that development of treatment modalities for infectious diseases is complicated by the complexity of this cytokine network. In the last decade numerous reports have presented data, often conflicting, which clearly demonstrate a role for TNF in the response to infections caused by viruses. This review summarizes this rapidly growing volume of data, discussing consistencies and discrepancies as appropriate. By better understanding the role of TNF in the host immune response, it may be possible to modulate this complex network for the benefit of the host in its battle against viral infection.