A major challenge in Medical Science has always been capturing targets for drug development. The state-of-the-art in targeting of RNA is the use of oligonucleotide-based modalities that target RNA sequence. Our focus over the past 15 years has been on developing technologies to decipher which cellular RNAs are “druggable” targets for small molecules and which small molecules can target them, serving as lead medicines. I will describe advances in the area of Small Molecules Interacting with RNA (SMIRNAs), including a sequence-based small molecule rational design tool dubbed Inforna. This approach allows sequence-based design principles for SMIRNAs of which only oligonucleotides have been previously designed from sequence. Inforna has enabled the design of SMIRNAs against RNAs that cause hard to treat cancers and incurable genetically defined diseases that have no known treatment. We will describe these compounds and their implications for leveraging known biology to advance lead medicines and also their implications as chemical probes to understand previously unknown RNA biology. I will also describe the development of approaches that allow for targeted degradation of RNAs in cells and animals by using SMIRNAs. For example, we have developed an approach that allows small molecules to recruit cellular nucleases to an RNA target to cleave it selectively and sub-stoichiometrically. Collectively, these studies show that small molecules can be designed to target RNA by using sequence-based design to deliver efficacious compounds targeting RNA including targeting the RNA for enzymatic destruction in cells and animals.