This review discusses the complex interplay between interferons (IFNs) and four medically important viruses—influenza, hepatitis C, herpes simplex, and vaccinia—highlighting the diverse strategies viruses employ to counteract the host's antiviral response. IFNs, known for their antiviral properties, are also potent regulators of cell growth and immunomodulatory agents. They exert their effects through the activation of type I and type II IFNs, which bind to specific receptors on the cell surface, triggering a signaling pathway that leads to the expression of hundreds of IFN-stimulated genes (ISGs). These ISGs play a crucial role in establishing an antiviral state in the host cell. Viruses have evolved mechanisms to counteract the IFN response, including direct interference with IFN receptor function, blocking receptor binding of IFNs, perturbing intracellular signaling pathways, and downregulating the expression of ISGs. For example, influenza virus uses the NS1 protein to disrupt the IFN response by inhibiting PKR activity and regulating the function of IFN-regulatory factors (IRFs). Hepatitis C virus (HCV) encodes proteins that interact with and inhibit PKR, and NS5A targets the IFN signaling pathway by disrupting the cross-talk between mitogen-activated protein kinase (MAPK) and JAK-STAT pathways. The review also discusses the role of functional genomics and bioinformatics in understanding virus-host interactions and the development of new antiviral therapies. High-throughput technologies, such as DNA microarrays, have revealed a much larger number of IFN-regulated genes than previously thought, providing a more comprehensive view of the host response to viral infection. This knowledge is essential for identifying new targets for therapeutic intervention and developing more effective antiviral strategies.This review discusses the complex interplay between interferons (IFNs) and four medically important viruses—influenza, hepatitis C, herpes simplex, and vaccinia—highlighting the diverse strategies viruses employ to counteract the host's antiviral response. IFNs, known for their antiviral properties, are also potent regulators of cell growth and immunomodulatory agents. They exert their effects through the activation of type I and type II IFNs, which bind to specific receptors on the cell surface, triggering a signaling pathway that leads to the expression of hundreds of IFN-stimulated genes (ISGs). These ISGs play a crucial role in establishing an antiviral state in the host cell. Viruses have evolved mechanisms to counteract the IFN response, including direct interference with IFN receptor function, blocking receptor binding of IFNs, perturbing intracellular signaling pathways, and downregulating the expression of ISGs. For example, influenza virus uses the NS1 protein to disrupt the IFN response by inhibiting PKR activity and regulating the function of IFN-regulatory factors (IRFs). Hepatitis C virus (HCV) encodes proteins that interact with and inhibit PKR, and NS5A targets the IFN signaling pathway by disrupting the cross-talk between mitogen-activated protein kinase (MAPK) and JAK-STAT pathways. The review also discusses the role of functional genomics and bioinformatics in understanding virus-host interactions and the development of new antiviral therapies. High-throughput technologies, such as DNA microarrays, have revealed a much larger number of IFN-regulated genes than previously thought, providing a more comprehensive view of the host response to viral infection. This knowledge is essential for identifying new targets for therapeutic intervention and developing more effective antiviral strategies.