Interferons (IFNs) are key cytokines with multifaceted antiviral and immunoregulatory properties. Three distinct types of IFN are recognized (I–III) based on structural features, receptor, cellular source and biological activities. The action of IFNs is mediated by a complex, partially overlapping, transcriptional program initiated by the interaction with specific receptors. Genetic diversity, with polymorphisms and mutations, can modulate the extent of IFN responses and the susceptibility to infections. Almost all viruses developed mechanisms to subvert the IFN response, involving both IFN induction and downstream effector mechanisms. Interactions between IFN types may occur, for both antiviral and immunoregulatory effects, in a complex interplay, involving both synergistic and antagonistic effects. In this paper, the aspects of IFN genetic diversity, viral strategies to counteract the IFN and synergistic and antagonistic interactions between IFN types are reviewed, in order to better understand the antiviral effect of interferon.