Co-evolution of viruses with their hosts for millions of years has led to a host immune system of high complexity and, likewise, sophisticated viral mechanisms to antagonize immunity. Early cytokines, such as interferons (IFNs), which integrate innate and adaptive immune responses, are essential targets for viruses. Viral antagonists that interfere with numerous components of the IFN system provide superb tools to explore the pathways and the connectivity of the IFN network. Here, the inhibition of type I IFN production by negative strand RNA viruses and IFN signaling by cytomegalovirus are discussed, illustrating unappreciated links between type I and type II IFN signaling. Viral principles might pave the way to develop new therapeutics to modulate immune functions.