RNA-protein interactions play critical roles in cellular regulatory processes and in the life cycles of many pathogenic viruses including HIV, hepatitis C, SARS, and West Nile virus, and thus represent attractive targets for therapeutics. We have developed novel cell-based assays to identify drugs that target the RNA-protein interactions. The assays incorporate a system of genetic reporters to accurately recapitulate RNA-protein interactions and enable screens with high sensitivity and specificity. In an initial test of the system, the HIV Rev-RRE interaction was successfully targeted with control inhibitors of the RNA-protein interaction. Experiments to optimize and convert the drug screening assays to high throughput format are currently in progress. The assays will be tested by screening a combinatorial library of RRE-binding peptides to be followed by a high-throughput chemical compound library screen. The development of high-throughput genetic methods to identify specific inhibitors of RNA-protein interactions is expected to help in the discovery of drugs directed against novel therapeutic targets.