Abstract: RNA has been considered a challenge to recognize selectively with small molecules. We have taken a non-traditional approach to define the RNA motifs privileged for binding small molecules, which has proven to be broadly successful. Our approach is not focused on a single target, as in traditional methods, but focused on using privileged RNA motif-small molecule interactions to dictate the cellular RNA target. To define these interactions, we developed an ultra-high throughput library-versus-library screen dubbed Two-Dimensional Combinatorial Screening (2DCS), affording an annotated library of druggable RNA motifs and small molecules to drug them. These data are mined against the human transcriptome to identify disease-causing RNAs that have druggable RNA motifs that are bound by small molecules. Collectively, our lead identification strategy, Inforna, has defined precise small molecules that target various RNAs involved in incurable or difficult-to-treat diseases and have helped to demonstrate that RNA is indeed druggable with small molecules. This approach could evolve into a general method to identify lead compounds that target RNA. These studies, we believe, have shown that sequence-based design can take a disease-causing biomolecule’s sequence and provide a lead medicine too target it.