Background: Leptomeningeal disease (LMD) is a complication that results from solid tumor metastasis. Prognosis is extremely poor. As therapeutic options for solid tumors improve, the rate of LMD continues to increase. Until recently, treatment has been limited to radiation therapy, intrathecal chemotherapy, and systemic chemotherapy, with an overall survival of 2-3 months. Targeted molecular therapy and immunotherapies are promising new options for increasing overall survival and clinical improvement; however, optimal clinical management remains unknown.; Methods: In this review, we discuss targeted molecular therapy and immunotherapy treatment options for LMD resulting from primary lung, breast, and melanoma tumors. In addition, we summarize dosing strategies, overall survival, clinical outcomes, and novel approaches to treatment.; Results: Our review indicates a deficiency in the current literature. Presently, intrathecal trastuzumab administration may be an effective option for patients with HER2-positive breast cancer. BRAF inhibitors and cytotoxic T lymphocyte-associated antigen-4 targets have shown promising results in LMD resulting from melanoma. Finally, tyrosine kinase inhibitors may increase overall survival in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. Pulsatile drug administration or dual therapy may be beneficial for patients who progress to LMD while being treated with EGFR targets for their primary malignancy.; Conclusion: Targeted molecular therapy and immunotherapy in LMD may provide favorable treatment options. Current literature is lacking in safety, efficacy, and overall response rates from the use of targeted therapy. Research is needed to draw significant conclusions about the most appropriate therapy for patients with LMD.