In recent years, there has been notable progress in identifying compounds that specifically interact with and modulate RNA, paving the way for their potential clinical application. This section delves into the methodologies employed in the quest for small molecules targeting RNA, highlighting both successful strategies and challenges faced in this field. We examine the advantages and limitations associated with various screening approaches and discuss key factors influencing the outcomes of RNA-targeted screening projects. Effective screening methodologies have enabled the identification of RNA-binding small molecules capable of modulating RNA function. These methods include high-throughput screening (HTS), fragment-based screening, and structure-based design approaches. HTS, in particular, allows for the rapid screening of large compound libraries against RNA targets, facilitating the discovery of lead compounds with desired binding affinity and specificity. However, the efficacy of these screenings is heavily reliant on the quality and diversity of the compound libraries used. Currently, the availability of RNA-focused compound libraries remains limited, posing a significant hurdle in the search for potent RNA ligands. Moreover, understanding RNA structural dynamics is critical for designing effective RNA-targeting therapeutics. RNA molecules exhibit complex folding patterns and dynamics that influence their binding interactions with small molecules. Advances in biochemical and structural analyses, coupled with computational modeling, are essential for predicting and optimizing RNA–ligand interactions. Nonetheless, challenges persist in accurately predicting RNA structure and dynamics, which can impact the success of screening efforts. To overcome these challenges, integrating high-throughput screening techniques with enhanced biochemical, structural, and computational analyses of RNA targets is crucial. This integrative approach promises to accelerate the discovery and optimization of RNA-targeting therapeutics by providing comprehensive insights into RNA–ligand interactions and enhancing the predictability of compound efficacy. Ultimately, advancing our understanding of RNA biology and therapeutic development hinges on overcoming these obstacles and leveraging multidisciplinary approaches to unlock the full potential of RNA as a therapeutic target.