AbstractDirect targeting of RNA with small molecules represents a novel and promising route to drugging the undruggable. RNA can adopt complex folds amenable to small molecule binding and, in turn, modulating biological activities such as gene expression and alternative splicing. However, targeting RNA directly with small molecules presents novel challenges. The transcriptome is vast and identifying regions of RNA that can both bind small molecules and modulate a desired biological outcome presents unique challenges. Further, RNA is intrinsically very dynamic, adopting a range of conformations with different populations and lifetimes. These can, in turn, give rise to an ensemble of different interaction surfaces. Finally, the composition of four repeating units and a highly negatively charged backbone provides challenges and opportunities for identifying potent and selective small molecule binders. Here, we describe how the dynamic, atomic-resolution, ensemble description of RNA can address these challenges in a repeatable and structure-guided manner.