Leptomeningeal cancer (LMC), which refers to involvement of the cerebrospinal fluid by cancer cells, is a poor prognostic sign that complicates various solid malignancies. Treatment of LMC evolved around brain radiation, intrathecal therapy, and systemic chemotherapy, but response rates are unsatisfactory, and patients usually die from cancer progression. In this article, we review the history of the major therapeutic approaches used to treat LMC, and we expand on the promising new venues for applying biologic targeted agents to the treatment options utilized in LMC.