Meningiomas arise from arachnoid cells and account for approximately 30% of all primary intracranial tumors. Most meningiomas (80-90%) are categorized as benign tumors (WHO grade I), with the remaining 10-20% being atypical (WHO grade II) or malignant (WHO grade III). Gross total resection offers the best chance of cure. Unfortunately, for meningiomas that are difficult to access, complete resection often cannot be achieved safely. In patients whose tumors are incompletely resected, recurrence is common, approaching 70% with 10–15 years of follow-up; in the case of atypical and malignant meningiomas, the time to recurrence is shorter and long-term survival rates are low. There are no established treatments for recurrent meningioma when surgical and radiation options are exhausted and current experience with chemotherapy and various targeted therapies is disappointing. Therefore, novel therapeutic strategies which can be combined with surgery need to be developed to control tumor growth. This application is directed towards developing new therapeutic options for meningiomas in a high throughput small (HTS) molecule screening system using the NINDS custom collection II library consisting of 1040 drugs and bioactive compounds, FDA-approved, which cross the blood-brain barrier (BBB). In our primary screening, we identified drug candidates that were specifically toxic to meningioma cells. These promising preliminary data stimulate us to further evaluate the effect of these candidates on meningioma tumor models in mice and explore the possible molecular mechanism(s) of tumor inhibition mediated by these candidate drugs.