Traditional drug discovery approaches for antiviral agents have focused on direct-acting inhibitors of viral targets, usually enzymes. When small-molecule inhibitors bind to the enzyme, usually the active site, they create loss-of-function viral proteins. Therefore, when a drug-resistant genome is 'born' within the cell due to the low fidelity of viral polymerses, especially for RNA viruses, its protein products are resistant to the effects of the drug and the drug-resistant genome can be propagated, escaping the cell in which it was first synthesized. We have learned that, for some small molecules, the drug-protein complex can become a dominant disrupter the growth of other viruses in the cell, even those that themselves encode drug-resistant protein. The goal of my laboratory is to identify mechanisms of antiviral targeting in which drug-protein complexes become dominant inhibitors of the outgrowth of drug-resistant viruses. I look forward to discussion with scientists in other disciplines about the applications of this paradigm to small-molecule inhibitors bacteria, eukaryotic and cancer genomes: if the small molecules target shared products and confer gain-of-function phenotypes, selection for drug-resistant genomes could be suppressed.