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The type I interferon (IFN) response protects cells from invading viral pathogens by triggering the transcription of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified, relatively few have been characterized with respect to antiviral activity. For most, little is known about their antiviral potential, their target specificity, and their mechanisms of action. We have established an overexpression screening platform to evaluate the antiviral potential of more than 350 ISGs against a diverse panel of animal viruses spanning the viral phylogeny. To date, we have screened 13 plus-strand RNA viruses, 7 negative-strand RNA viruses, and one DNA virus. Hierarchical clustering of top ISG hits indicates that viruses segregate based on their genomic content, with plus-stranded RNA viruses exhibiting the highest sensitivity to the greatest number of ISGs. We have also probed the mechanisms of action of select antiviral ISGs against hepatitis C virus, dengue virus, and influenza A virus. Many of these ISGs feed back into antiviral programs, while others appear to have more targeted effector functions. Using a variety of experimental techniques, we show that inhibition of early viral life cycle events is a common mechanism targeted by numerous IFN effectors. Gaining additional insight into the cellular and biochemical mechanisms if ISG-mediated inhibition may provide a platform for the development of novel antiviral therapies. [ABSTRACT FROM AUTHOR]