Neoplastic meningitis is an increasingly recognized complication of advanced metastatic cancer and, if left undiagnosed or untreated, is characterized by rapid neurologic deterioration and death. Thus, the diagnosis and treatment of neoplastic meningitis present challenges for the clinical oncologist. The diagnosis of neoplastic meningitis is based on clinical signs and symptoms, laboratory analysis of cerebrospinal fluid to determine cell count and cytology, and analysis of neuroimaging studies for evidence of leptomeningeal or cranial nerve enhancement. Once diagnosed, conventional treatment regimens may include radiotherapy combined with systemic or intrathecal chemotherapy, often with the antimetabolites cytarabine and/or methotrexate. However, the prognosis for neoplastic meningitis secondary to an underlying solid tumor or recurrent leukemia is poor with conventional treatment regimens. Therefore, novel agents for intrathecal administration, including DepoCyttrade mark, mafosfamide, and topotecan, or novel therapeutic approaches, including conjugated monoclonal antibodies and immunotoxins or gene therapy, are currently under investigation. Such new agents and therapeutic approaches will facilitate the development of effective treatment strategies and will ultimately improve the outcome for patients with this devastating disease. This article provides an overview of the approaches to the diagnosis, evaluation, and treatment of neoplastic meningitis.