Interferons (IFNs) comprise type I, II and III families with multiple subtypes. Via transcription of IFN-stimulated genes (ISGs), IFNs can exert multiple biological effects on the cell. In infectious and chronic inflammatory diseases, the IFNs and their ISG sets can be potentially utilized as biomarkers of disease outcome. Animal models allow investigations into disease pathogenesis and gene knockout models have proved cause and effect relationships of molecules related to the IFN response. Sets of IFN subtypes and their ISG products provide immunological signature patterns for different viral and other diseases. In this article, we give an overview of IFNs in several virus infection models and autoimmune diseases of medical relevance. Lessons learned from animal models inform us of IFN system parameters as indicators of disease outcome and whether clinical research is warranted. Moreover, validated IFN biomarkers for prognosis enhance our understanding of therapeutic and vaccine development.