The innate immune system requires the activity of interferon-stimulated genes (ISGs) to mount its protective response against viruses and other pathogens. However, the sensitivity of ISGs against viruses varies widely, and the spectrum of antiviral activities of ISGs is only partially understood. Utilizing an arrayed, time-resolved loss-of-function screen, we systematically investigated 285 ISGs for their virus-modulating activity against eight viruses.