Leptomeningeal metastasis occurs in ~5% of all patients with cancer and is the third most common metastatic complication of the central nervous system. Staging of leptomeningeal metastasis includes contrast-enhanced brain and spine magnetic resonance imaging and radionuclide cerebrospinal fluid (CSF) flow study. Treatment, when clinically indicated, often requires administration of involved-field radiotherapy to bulky or symptomatic disease sites as well as intra-CSF and systemic chemotherapy. The use of high-dose systemic therapy may benefit selected patients with breast- or lymphoma-related leptomeningeal metastasis and obviate the need for intra-CSF chemotherapy. Intra-CSF drug therapy primarily utilizes one of three chemotherapeutic agents (e.g., methotrexate, cytosine arabinoside, and thiotepa) administered by a variety of schedules either by intralumbar or intraventricular drug delivery. Beginning to be utilized are novel intra-CSF agents, such as the targeted monoclonal antibodies rituximab (anti-CD20 for B-cell lymphoma-related leptomeningeal metastasis) and trastuzumab (anti-Her2/neu for breast cancer-related leptomeningeal metastasis). Although treatment of leptomeningeal metastasis is palliative with median patient survival of 2 to 3 months, treatment may afford stabilization and protection from further neurologic deterioration in patients with leptomeningeal metastasis.