Leptomeningeal metastasis (LMD) is a lethal complication caused by a variety of cancers, typically developing late in the disease course. It is associated with major neurologic disabilities and short survival. The incidence of LMD may increase because of longer survival of patients who have cancer, and because of the use of newer large-molecule therapies with poor central nervous system penetration. To achieve improved outcomes for patients who have LMD, new treatments need to reach the meninges and cerebrospinal fluid and interact with relevant molecular targets. Some of the agents currently in testing may contribute to this goal. To allow for better outcomes through earlier treatment, advances in diagnosis are needed. By using agents with higher therapeutic indices, in patients with a lower burden of disease (identified earlier with clinical or molecular markers) it should be possible to achieve gradual improvements in outcomes for patients suffering from this devastating disease.