Neoplastic meningitis (NM) is a dreaded metastatic complication occurring in 5% to 10% of cancer patients. Survival is limited, usually ranging from 4 to 16 weeks. The pathogenesis of NM has not been extensively investigated but can be considered from the anatomic and molecular biologic standpoints. Malignant cells reach the cerebrospinal fluid (CSF) and meninges by direct invasion from tumors located near or within the central nervous system (CNS), or via the bloodstream or other pathways that contact the CNS. Symptoms of NM are caused by malignant cells invading and damaging nervous tissue, obstructing the vascular supply to nervous tissue, or obstructing CSF pathways. The molecular changes responsible for the development of NM are not well delineated, but it is likely that they involve changes in molecules responsible for tumor cell adhesion, migration, and proliferation. An understanding of the pathogenesis of NM will allow for its earliest possible diagnosis and ultimately lead to therapies targeted at the underlying molecular causes of this devastating condition.