The field of RNA biology has recently made significant strides, revealing its vital involvement in various diseases, from infections caused by viruses and bacteria to cancer and neurological conditions. This insight has spurred interest across numerous research groups in crafting small molecules akin to drugs that can interact with RNA. Nevertheless, targeting RNA presents several unique obstacles. RNA’s dynamic nature and its lack of chemical diversity pose significant challenges. Moreover, the process often leads to the identification of non-selective RNA-binding ligands during screening efforts. This section delves into crucial considerations and breakthroughs in the development of small molecules aimed at RNA, spanning the essential chemistry to notable examples of small molecules that have shown clinical success. We begin our exploration by delving into the various functional categories of RNA, as well as its structural complexities and dynamic properties. Next, we will discuss the fundamental principles of RNA recognition, the techniques used for screening small molecules, and the methodologies for determining RNA structure. Following this, we will tackle the unique challenges and innovative strategies involved in designing ligands that target RNA, considering the perspectives of both RNA and small molecules. Finally, we will highlight some of the most significant and impactful examples in this field to date.