RNA structure plays a role in nearly every disease. Therefore, approaches that identify tractable small molecule chemical matter that targets RNA and affects its function would transform drug discovery. Despite this potential, discovery of RNA-targeted small molecule chemical probes and medicines remains in its infancy. Advances in RNA-focused libraries are key to enable more successful primary screens and to define structure-activity relationships amongst hit molecules. In this review, we describe how RNA-focused small molecule libraries have been used and evolved over time and provide underlying principles for their application to develop bioactive small molecules. We also describe areas that need further investigation to advance the field, including generation of larger data sets to inform machine learning approaches.