Surgical resection and radiotherapy form the backbone of effective treatments for meningioma. The majority of patients have WHO Grade I tumors that can be successfully treated with local therapies, with low relapse rates. However, patients with Grade II and III tumors have higher rates of relapse despite surgery and radiation. Repeat surgeries and radiotherapy can be used for salvage, but when such options have been exhausted, systemic treatments are considered. Unfortunately, there have been no systemic therapies to date that are definitively proven to prolong survival. Small patient populations, varied outcome measures, and lack of control populations have limited the evaluation of systemic therapies in recurrent and refractory meningiomas. Given the slow-growing nature of these tumors, it is often difficult to determine whether a given systemic therapy has changed the natural history of the disease. Multiple cytotoxic, hormonal, immunologic, and antiangiogenic agents have been trialed in small, prospective single arm studies, but no agent has received FDA approval to date. Current NCCN guidelines recommend considering three of these agents: interferon-alpha-2 beta, somatostatin analogues, and sunitinib in patients who require systemic therapy. However, providers should be aware that the activity and impact of such agents on the natural history of the disease is unclear. In this chapter we will review the available data on the use of systemic therapy in patients with meningiomas who have exhausted radiotherapy and surgical options.