A novel optical-based high-throughput screening technology has been developed for increasing the rate of discovering chemical leads against RNA targets. SCAN ( Screen for Compounds with Affinity for Nucleic Acids) is an affinity-based assay that identifies small molecules that bind and recognize structured RNA elements. This technology provides the opportunity to conduct high-throughput screening of a new class of targets-RNA. SCAN offers many attractive features including a simple homogeneous format, low screening costs, and the ability to use common laboratory equipment. A SCAN assay was developed for the HCV IRES Loop IIId RNA domain. A high-throughput screen of our entire compound library resulted in the identification of small molecule ligands that bind to Loop IIId. The Z' values were greater than 0.8, showing this to be a robust high-throughput screening assay. A correlation between SCAN EC50 and KD values is reported suggesting the ability to use the assay for compound optimization.