Platinum compounds such as cisplatin and oxaliplatin are in broad clinical use. While highly effective against certain cancers, efficacy is limited by toxicity and resistance against these small metal compounds. We and others have shown extensive interactions of Pt(II) compounds with cellular RNAs, demonstrating potential for therapeutic Pt(II) compounds to act outside of the textbook DNA damage response. One remarkable example is the ability of oxaliplatin-like Pt(II) compounds to specifically induce the nucleolar stress response. The nucleolus is the manufacturing site for ribosomes and a hub of cell signaling. Perturbations of the oxaliplatin diaminocyclohexane ligand have surprisingly selective results, suggesting that a relatively specific interaction is disrupted by platinum compounds that cause nucleolar stress. Current efforts include high resolution expansion microscopy to track the influence of Pt(II) compounds on nucleolar morphology, and developing a click-enabled Pt(II) compound library as tools for target identification, with an aim to determine the molecular mechanisms of action of these small molecule platinum compounds that specifically induce nucleolar stress.