Studies of the action of interferon-stimulated genes (ISGs) and their protein products have resulted in fundamental discoveries relevant to translational control, regulation of RNA stability and editing, and protein transport and turnover. Actions of ISGs will remain critical to improved clinical application of agonists and antagonists of the toll-like receptor and the interferon signaling cascades-now 25 years after the U.S. Food and Drug Administration and worldwide regulatory approval of the pharmaceutical product produced by recombinant DNA technology. Because the antiviral and cellular actions of these several hundred genes (what?) and their protein products are now being functionally (how?) further elucidated but have been comprehensively summarized to only limited extents, we have selected some of the most potently induced ISGs for review in this special issue of the Journal of Interferon Cytokine Research.