Xu et al deliver three pioneering advances: First, they ascribe a pyrimidine‐enriched transcriptome specifically to NF2-altered mesothelioma; second, they demonstrate that YAP directly binds the CAD promoter and a DHODH enhancer, markedly increasing de novo pyrimidine biosynthesis pathway flux and creating a vulnerability to DHODH inhibitors; lastly, they demonstrate potent in vivo synergy of such compounds with cisplatin, lending hope for possible future integration of pyrimidine pathway blockade into current treatment regimens (Fig. 1). Here, NF2 is linked to mesothelioma.