Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies. In this manuscript by CGM investigator Vijaya Ramesh and colleagues, data from previous high-throughput drug screening in NF2 preclinical models was leveraged to identify a class of compounds targeting the ubiquitin-proteasome pathway (UPP) that may have utility in NF2. Through a series of elaborate investigation of these UPP targeting agents in vitro and in vivo, the group found that treatment delayed tumor growth, suggesting a therapeutic potential. This important work in preclinical models lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.