RNA-binding motif protein 39 (RBM39) is an RNA-binding protein involved in transcriptional co-regulation and alternative RNA splicing. Recent studies have revealed that RBM39 is the unexpected target of aryl sulphonamides, which act as molecular glues between RBM39 and the DCAF15-associated E3 ubiquitin ligase complex leading to selective degradation of the target. Loss of RBM39 leads to aberrant splicing events and differential gene expression, thereby inhibiting cell cycle progression and causing tumour regression in a number of preclinical models. Many clinical studies have shown that aryl sulphonamides were well tolerated, but their clinical performance was limited due to an insufficient understanding of the target, RBM39 biology and a lack of predictive biomarkers. This review summarises the current knowledge of RBM39 function and discusses the therapeutic potential of this spliceosome target in cancer therapy.