In the present study, we aimed to mimic the beneficial actions of STAT1 modification with a small molecule that also enhances the activity of the IFN signaling pathway. We describe here the development of a high-throughput screening (HTS) system for novel small molecular weight compounds (so-called ''small molecules'') that might increase ISG expression and antiviral activity. To develop this screening system, we generated cell lines that stably express the human interferon-stimulated response element (ISRE) driving a luciferase reporter gene. The ISRE gene promoter element is responsible for type I IFN signaling that mediates host defense against a wide range of viruses [15, 16] . After establishing that the ISRE-reporter cell line responded linearly to IFN-b concentration and treatment time, we converted the assay to an automated format for a screen against already approved or approvable drugs. We also screened a library of phosphatase inhibitors that might mediate increased STAT1 phosphorylationactivation. Our analysis identified a series of diverse compounds capable of significantly increasing ISRE activity. One compound in particular, the anthracycline antibiotic idarubicin hydrochloride, was used to explore mechanism of action and to validate the proposal that small molecules can enhance ISRE activity to drive higher levels of ISG expression and improved control of viral level. The findings provide for the concept that current antiviral therapeutics act directly and specifically on viral proteins whereas next-generation antivirals might act to enhance host immunity against a broad range of viruses. Either alone or together, these approaches might better address the current need for more effective treatment against common as well as new and emergent viral infections.