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This chapter reviews the role of toll-like receptors (TLRs) in innate antiviral responses and in coordinating the antiviral adaptive immune system, and discusses the potential for TLRs as novel molecular targets for antiviral immunomodulatory therapy. A mutation in the Toll gene in Drosophila that results in defective protein was associated with reduced survival after fungal infection. The chapter discusses TLR recognition of pathogen-associated molecular patterns, TLR signaling pathway, biological outcomes of TLR activation, and TLRs and the pathogenesis of selected viral pathogens. The potential role for TLR-7 and TLR-8 in HSV pathogenesis is highlighted by ongoing research efforts to control herpes simplex virus (HSV) infections with the use of small-molecule TLR-7 and TLR-8 agonists. Many viruses, however, have evolved to develop strategies that block the effector mechanisms induced through TLR signaling pathways. Coronavirus, a contagious viral pathogen that causes the highly fatal severe acute respiratory syndrome (SARS), has an attenuated ability to induce type I interferons (IFNs), which are essential for the efficient control of the infection, because it has developed a TLR evasion mechanism characterized by failure of IRF-3 activation. The chapter describes TLRs as targets for immunomodulation and antiviral therapies. The successful clinical development of imiquimod, the prototype TLR immune response-modifying drug, provides a solid example of the promise and remarkable potential that TLR modulators have in bringing novel antiviral therapeutic strategies in the clinical setting.