An emerging body of evidence indicates that post-transcriptional gene regulation relies not only on the sequence of mRNAs but also on their folding into intricate secondary structures and on the chemical modifications of the RNA bases. These features, which are highly dynamic and interdependent, exert direct control over the transcriptome and thereby influence many aspects of cell function. Here, we consider how the coupling of RNA modifications and structures shapes RNA–protein interactions at different steps of the gene expression process.