RNA-binding proteins (RBPs) are central to RNA metabolism and play pivotal roles in health and disease across all domains of life. Despite their therapeutic potential, targeting RNA-binding domains (RBDs) with small molecules remains challenging due to their extended interaction surfaces and/or dynamic binding properties. Here, I will present strategies developed by the Kwan and Ataide laboratories to modulate two representative RBPs: FtsY from Escherichia coli, an antibiotic target, and Nsp9 from SARS-CoV-2, an antiviral target. We have identified nucleic acid (NA) mimics that bind to the RBD of FtsY and Nsp9 with sub- to mid-micromolar affinities, with some compounds demonstrating whole-cell activity. I will discuss the biophysical and biochemical characterization of selected NA mimics and their interactions with FtsY and Nsp9. Finally, I will compare the strengths and limitations of different approaches for discovering RBP modulators and explore their broader potential for targeting diverse classes of RBPs.