RNA-binding proteins (RBPs) regulate RNA during various processes such as transcription, splicing, chemical modification, trafficking, stability, degradation, and epigenetic processes. Together with their implications in disease, a strong impetus has emerged to uncover the broader regulatory functions of protein–RNA interactions. The tools available to study RBPs lack the throughput necessary to keep up with this rapidly growing class of structurally diverse molecular machines. This dissertation describes the development of a novel technology to assay the RNA-binding affinity of many variants of an RBP within a single tube using LC-MS. I used this technology to reveal novel RNA–binding residues within two different RBPs. In another assay, I identified novel RBPs associated with epigenetic processes that await further validation. The research presented herein has implications for the advancement of the fields of RNA biology and epigenetics.