The type I interferons (IFNs), IFN-α and -β, are key effector molecules of the immune response to viruses. The anti-viral action of IFNs on virus-infected cells and surrounding tissues is mediated by expression of hundreds of IFN-stimulated genes. Viperin (virus inhibitory protein, endoplasmic reticulum-associated, IFN-inducible) is an Interferon stimulated gene (ISG), which is induced by type I, II, and III IFNs or after infection with a broad range of DNA and RNA viruses. Recent evidence indicates that Viperin disrupts lipid rafts to block influenza virus budding and release and interferes with replication of hepatitis C virus by binding to lipid droplets, small organelles involved in lipid homeostasis that are essential for hepatitis C virus replication. Viperin is also induced by nonviral microbial products such as lipopolysaccharide (LPS) and by a wide range of bacteria, suggesting a broader role in innate antimicrobial defenses.