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Academic and industrial research groups employ a wide range of screening and lead generation techniques to discover molecules that bind RNA. In this chapter we review the methods and techniques used to screen RNA for small molecule binders, characterize their binding interactions, and measure the functional consequences of RNA ligand binding. The screening approaches covered include both knowledge-based (e.g. virtual screens) and agnostic (e.g. high-throughput screens), such as affinity selection mass spectrometry (ASMS), multitarget affinity/specificity screening (MASS), automated ligand identification system (ALIS), DNA-encoded libraries (DELs), small molecule microarrays (SMMs), fragment based drug discovery (FBDD), surface plasmon resonance (SPR), and phage display. Methods to confirm the binding of a ligand to an RNA target are also described including NMR methods, ITC, small-angle X-ray scattering (SAXS), Förster resonance energy transfer (FRET) assays, site-specific labeling assays, fluorescence indicator displacement (FID) assays, microscale thermophoresis (MST), and X-ray crystallography. Moreover, methods for target engagement along with binding site identification/target engagement are discussed. This chapter also explores functional assays used to determine if an RNA binder induces a desired pharmacological effect. Finally, the identification of a lead series is also explored along with examples of hit optimization from literature.