The goal of this chapter is to review the therapeutic approaches to patients with leptomeningeal metastases (LM). The goal of LM treatment is to prolong survival, to maintain quality of life, and to delay neurological deterioration. Intracerebrospinal fluid (CSF) pharmacotherapy, systemic pharmacotherapy, and mostly focal radiotherapy are the key treatment modalities. Until recently, no high-level evidence for the use of intra-CSF therapy in LM was available. Recently, a significant improvement of progression-free survival related to LM has been reported in a randomized phase III trial in breast cancer patients with LM using liposomal cytarabine in combination with systemic therapy compared with systemic treatment alone. The safety and efficacy of new, mostly targeted agents, such as trastuzumab, upon intra-CSF administration are currently being explored. Targeted treatments, such as anti-human epidermal growth factor receptor (HER) 2 treatments for breast cancer, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for non-small-cell lung cancer (NSCLC), or BRAF-targeted agents for melanoma, and immunotherapy for lung cancer and melanoma have an emerging role in the management of this condition. Radiotherapy should be given to relieve clinical symptoms and signs and for the treatment of meningeal nodules. Whole-brain radiotherapy should be avoided. Individualized supportive care strategies involving patients and caregivers are essential during the course of the disease.