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RNA–protein interactions control viral RNA replication, transcription, translation, and particle assembly. Progress toward understanding the functional significance of RNA–protein complexes in the viral life cycle is hindered by the lack of high resolution structural information. Challenges to acquiring structural data include RNA's inherent instability and conformational plasticity, coupled with the comparatively high cost of generating large quantities of RNA for biophysical experiments. The potential for successful structure determination is increased by conducting biochemical experiments that outline interacting domains and identify key residues. These approaches are aimed at defining and characterizing RNA and protein substrates that are suitable for high resolution structural analysis.