Purpose of Review <p>Leptomeningeal disease (LMD), or spread of cancer cells into the pia and arachnoid membranes encasing the brain and spinal cord, is associated with high symptom burden and poor survival at 2 to 5&#xa0;months. Conventional treatments including photon-based radiation therapy, systemic chemotherapy, and intrathecal chemotherapy demonstrate limited efficacy. Despite significant successes for a range of solid tumors, immunotherapy has not yet demonstrated significant efficacy in management of LMD. Advances in understanding of LMD pathophysiology, improved diagnostics, and novel therapeutics are shifting this paradigm. In this article, we review diagnostic and treatment challenges associated with LMD.</p> Recent Findings <p>We discuss the use of novel cerebrospinal fluid (CSF) analysis techniques such as circulating tumor cell and CSF cell-free DNA assessment to overcome limitations of conventional diagnostic modalities. We then review advances in treatment including clinical trial data demonstrating efficacy of proton craniospinal radiation to treat the entire neuroaxis. We discuss emerging data regarding targeted therapeutics conferring durable survival benefit.</p> Summary <p>Novel therapeutics and combinatorial treatment approaches will likely further improve outcomes for patients with LMD.</p>