The proteasome inhibitor bortezomib is used for multiple myeloma treatment, but drug resistance commonly develops. Dharminder Chauhan, Kenneth Anderson and colleagues reasoned that, rather than broadly inhibiting proteolysis, enhancing the proteolysis of particular oncogenes may be an alternative therapeutic strategy. They identified an inhibitor (P5091) of ubiquitin-specific protease 7 (USP7) that blocked MDM2 deubiquitylation by USP7 and thus stabilized p53. P5091 caused apoptosis and overcame bortezomib resistance in multiple myeloma cells in vitro and also slowed the growth of various multiple myeloma xenografts in mice.