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The study of RNA has grown tremendously in recent years. RNA has moved from being known as an intermediate in the central dogma of molecular biology to a molecule of enormous structural and functional diversity, implicated in every aspect of biology. With the rapid discovery of new functions, it is clear that RNA-targeting small molecule probes are needed to study RNA biology and elucidate the therapeutic potential based on RNA-small molecule interactions. While many techniques exist for measuring RNA-small molecule interactions, many of them have flaws that make them difficult to use routinely and are often not widely applicable. A new technique called Microscale Thermophoresis (MST), which measures the directional migration of molecules and/or molecular-ligand complexes along a temperature gradient, can be used to measure binding affinity using very small amounts of sample. The high sensitivity of the technique enables the measurement of affinity constants in the nanomolar and micromolar range.